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(Circulation Research. 1996;78:737-749.)
© 1996 American Heart Association, Inc.

Articles

₁-Adrenergic Receptor Subtypes

Molecular Structure, Function, and Signaling

Robert M. Graham, Dianne M. Perez, John Hwa, Michael T. Piascik

From the Victor Chang Cardiac Research Institute (R.M.G.), St Vincent's Hospital, Sydney, Australia; the Department of Molecular Cardiology (D.M.P., J.H.), Research Institute, Cleveland (Ohio) Clinic Foundation; the Department of Physiology and Biophysics (R.M.G., J.H.), Case Western Reserve University School of Medicine, Cleveland, Ohio; and the Department of Pharmacology (M.T.P.), University of Kentucky, Lexington.

	Introduction

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The ₁ARs are important mediators of sympathetic nervous system responses, particularly those involved in cardiovascular homeostasis, such as arteriolar smooth muscle constriction and cardiac contraction.^{1 2} In addition, ₁ARs have more recently been implicated in the pathogenesis of cardiac hypertrophy, in ischemia-induced cardiac arrhythmias, and in ischemic preconditioning.^{1 3} Like other ARs, ₁ARs are activated by the catecholamines, norepinephrine and epinephrine. They are intrinsic membrane glycoproteins and are members of the GPCR superfamily.

Over the past 10 to 15 years, data initially based on functional, radioligand, and biochemical studies have accumulated, indicating that the ₁ARs are a heterogeneous group of distinct but related proteins. This conclusion has been confirmed with the molecular cloning of three distinct ₁-receptor subtypes, although until recently discrepancies between the properties of the cloned expressed receptors and those characterized pharmacologically and biochemically have led to confusion in the classification of ₁-receptor subtypes and their coupled effector responses.

As detailed in the present review, much of this confusion has now been clarified for the three cloned ₁ARs. These and other recent insights into the molecular structure, function, and signaling of ₁ARs, the control of ₁AR-gene expression, and pharmacological evidence for additional ₁AR subtypes will be reviewed here. For additional information, the reader is also referred to several previous reviews of ₁ARs.^{4 5 6 7}

	1AR Subtypes

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Functional studies of AR responses, particularly from the laboratories of McGrath⁸ and Ruffolo,⁹ provided the initial evidence that there may be subtypes of ₁ARs. These studies indicated that postjunctional responses mediated by ₁ARs could not be explained adequately on the basis of a single population of receptors. This concept was further advanced by the radioligand binding studies of Morrow and Creese,¹⁰ who suggested a subdivision of ₁-receptors into _1A and _1B subtypes. This was based on the finding of different binding profiles for various ligands, with the agonist oxymetazoline and the antagonists WB-4101 and phentolamine being recognized with higher affinity at _1A- than at _1B-receptors. This subdivision was supported by findings of differential susceptibilities to covalent modification by the alkylating agents CEC and SZL-49, and the photoaffinity label aziodoprazosin, and by findings of differences in the biochemical mechanisms of receptor-mediated signaling and differences in the requirements of extracellular Ca²⁺ in signal transduction by ₁-receptor subtypes.^{6 1} On the basis of these considerations, the _1A subtype was defined as binding to WB-4101, phentolamine, and oxymetazoline with high affinity and to be insensitive to inactivation by CEC, to require Ca²⁺ influx for signaling, and to be expressed particularly in the vas deferens, hippocampus, and cerebral cortex. The _1B subtype, on the other hand, was considered to have a low affinity for WB-4101, phentolamine, and oxymetazoline, to be completely inactivated by CEC, to not require Ca²⁺ influx for signaling but rather to mobilize Ca²⁺ from intracellular stores, and to be expressed prototypically in rat liver, spleen, and cerebral cortex. Many additional ligands have subsequently been suggested to discriminate between these two ₁-receptor subtypes, with 5-methylurapidil, (+)niguldipine, methoxamine, and benoxathian being recognized with higher affinity at receptors classified, as described above, as _1A-receptors. Spiperone, a classical D₂ dopamine receptor antagonist, has also been reported to be recognized with higher affinity by _1B-receptors¹¹ ; abanoquil, with higher affinity at the _1AAR. However, the subtype selectivity of these agents has not been confirmed by others.^{12 13}

This classification, however, was complicated by the cloning of cDNAs or genes for three distinct ₁AR subtypes,⁶ encoding at least one and possibly two subtypes not recognized previously on the basis of pharmacological or radioligand binding studies. Recently, this confusion in the identity of the cloned subtypes vis-à-vis the pharmacologically defined subtypes has now been resolved. (A detailed consideration of the cloned ₁-receptors and their identity with pharmacologically defined tissue correlates is provided in Reference 6⁶ .) Thus, it is now widely agreed that the cloned _1bAR is identical to the pharmacologically defined _1BAR^{6 14} and that the cloned _1dAR,¹⁵ initially labeled as the _1aAR¹⁶ and then as the _1a/dAR,¹⁷ is a novel subtype not recognized previously on the basis of pharmacological or radioligand binding studies.² It is also now apparent that the _1d subtype is expressed in a variety of tissues, including vascular smooth muscle, cerebral cortex,^{15 16} and probably rat lung.¹⁸ In rat aorta and iliac artery, it appears to be the predominant subtype mediating vasoconstriction.^{12 19 20} On the basis of these considerations, we suggest that this subtype now be designated as the _1DAR (Tables 1 and 2). More recently, as a result of studies from several laboratories,^{13 21 22 23 24 25} it is apparent that the cloned _1cAR is the homologue of the pharmacologically defined _1AAR and should thus be reclassified² as either the _1AAR¹⁴ or _1A/cAR.³ This subtype appears to be the major receptor mediating vasoconstriction in rat mesenteric resistance and renal arteries.²⁰

View this table: [in this window] [in a new window]   Table 1. 1AR Subtype Classification

View this table: [in this window] [in a new window]   Table 2. Characteristics of the Cloned 1ARs

Presently, there are few ligands that are recognized by one ₁ subtype with at least a 100- to 1000-fold higher affinity than by the other two subtypes. However, some compounds of interest include 5-methylurapidil, which has an 80- to 120-fold higher affinity for _1A/cAR than for _1BAR and _1DAR,¹³ and oxymetazoline¹⁴ and A-61603,²⁶ which selectively activate _1A/c receptors (Table 2). A structurally modified (+)niguldipine compound, SNAP 5089, has a 100-fold selectivity for the _1A/c subtype²⁷ ; KMD-3213 has a 500-fold lower affinity at the _1BAR and a 56-fold lower affinity at the _1DAR than at the _1A/cAR (K_i, 0.036 nmol/L at the _1A/cAR)²⁸ ; and RS17053 has a 50- to 60-fold selectivity for the _1A/cAR (K_i, 0.29 nmol/L).²⁹ Spiperone and respiperone have been suggested to be _1B selective¹¹ but show only a 5- to 10-fold higher affinity for this subtype.¹² However, there are preliminary data to suggest that AH11110A may be a useful compound for identifying _1BARs, since it is more than 30-fold selective for the _1BAR than for either the _1A/cAR or _1DAR.³⁰ For the _1DAR, BMY 7378¹² and SKF 105854¹⁴ have been reported to be 50- to 100-fold selective compared with the other two subtypes. Of note, the pharmacological profiles of the various subtypes show little species differences. A possible exception is the cloned bovine _1A/c-receptor, which binds (+)niguldipine with a markedly lower affinity and WB-4101, prazosin, and phentolamine with an 10-fold lower affinity than its rat homologue. Moreover, the higher affinity of the cloned rat _1A/c-receptor for (+)niguldipine is in accordance with the affinity of this compound defined previously from functional or radioligand binding studies of the _1AAR in rat tissues.¹³

	Other Subtypes

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In addition to the _1A/c-, _1B-, and _1D-receptors, there is now also considerable pharmacological evidence for additional subtypes. This came initially from the studies of Holck et al³¹ and later from the studies of Flavahan and Vanhoutte,³² who identified ₁ARs that recognized the ligand prazosin with either high (_1H) or low (_1L) affinity. More recently, largely on the basis of functional studies of vasoconstrictor responses in various vascular beds, Muramatsu et al³³ have extended this concept to incorporate the previously defined _1A/c-, _1B-, and _1D-receptors, which all bind prazosin with high affinity, into the _1H group. In addition, these investigators have provided evidence that the sites with low affinity for prazosin, the atypical or _1L group, can be subdivided into those receptors that recognize yohimbine and the novel ₁AR antagonist, HV732, with low affinity, which are classified as _1L-receptors, and those receptors that have both a moderate affinity for yohimbine and a high affinity for HV732, which are termed _1N-receptors.³³ Although the final acceptance of the _1L group as distinct ₁ARs will ultimately require their molecular cloning, ₁-like receptors with low affinity for prazosin may not be confined to blood vessels but may also contribute to ₁AR responses in rat parotid gland, guinea pig ileum and nasal mucosa, and canine and human prostate.³⁴ When these or other ₁AR subtypes are fully characterized using functional, radioligand binding, and molecular biology techniques, it has been suggested that they be added to the current ₁AR classification scheme as the _1EAR, _1FAR, etc.¹⁴

	Evaluation of AR Subtypes

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From the above considerations, it is apparent that the evaluation of ₁AR responses or of potential tissue, species, and developmental differences in subtype expression is still difficult. Evaluation of subtype expression at the mRNA level is somewhat easier but is still confounded by the low abundance of message for all subtypes in most tissues. This necessitates the extraction of large amounts of total RNA or preferably the isolation of poly(A⁺) RNA for Northern blot analyses. In addition, great care must be taken to verify that the probes used are subtype specific and are radiolabeled to high specific activity. For this reason, cRNA probes are preferable to cDNA probes. Amplification of mRNA by RT followed by PCR has been used to overcome the problem of low mRNA abundance.^{13 23} However, even with the use of internal controls, this method is generally only semiquantitative. It may also result in false positives due to the detection of illegitimate transcription (ie, the transcription of very low levels of message that can occur in tissues that lack detectable ₁AR-mediated responses) or to false negatives due to poor primer selection or the use of primers that are not species specific. In addition, the products obtained by RT-PCR should ideally be verified by restriction mapping, sequencing, or Northern analysis.¹³ Analysis by RNase protection assay or DNA solution–phase hybridization is thus widely used to detect expression of ₁AR subtypes and can provide a quantitative measure of mRNA abundance.^{13 21 22 35} Table 3 shows the abundance of mRNA for ₁AR subtypes in various tissues, as reported in different studies using one or other of the above approaches. Although there is some variance in the reported levels of subtype expression, which likely reflects the different techniques used, there is good agreement that the _1A/cAR is expressed in human heart and liver and in rat heart, lung, vas deferens, and salivary gland but is not expressed at all in rat spleen or liver. This latter finding in rat liver contrasts with the abundant expression of the _1A/cAR in rabbit liver.³⁶ In addition, the not uncommonly found discordance between mRNA expression and the expression of receptor protein that is evident from the characterization of ₁AR-mediated functional responses is apparent from the low and variable expression of _1A/cAR mRNA in rat kidney. In this tissue, the _1A/cAR is clearly the dominant subtype mediating vasoconstriction.²⁴ For the _1BAR, mRNA expression is uniformly high in rat heart and liver and is low or absent in rat hippocampus, salivary gland, and aorta. This finding in rat aorta is not surprising, since presently there are no studies that clearly document _1BAR-mediated vasoconstrictor responses in the rat in vivo. The _1DAR receptor is clearly expressed in rat vas deferens and aorta as well as in human aorta and is expressed at very low levels, if at all, in human and rat liver and in rat kidney, spleen, and salivary gland (Table 3).

View this table: [in this window] [in a new window]   Table 3. Abundance of mRNA for 1AR Subtypes in Various Tissues

Because the recently developed subtype-selective compounds mentioned above are still only moderately selective, or are not yet fully characterized, identification of ₁ subtypes by radioligand binding or functional studies remains even more problematic than characterization at the mRNA level. Presently, this requires detailed evaluations using several compounds in noncumulative concentration-effect studies or in complete competition binding assays (see Reference 24²⁴ for examples). It should also be noted that several of the recently developed subtype-selective compounds may be of limited use in vivo, since they are poorly specific for ₁AR and may thus block or activate other adrenergic or nonadrenergic receptors. Even prototypical compounds, such as prazosin (₁-selective antagonist) and yohimbine (₂-selective antagonist), must be used with caution, since they can be recognized with reasonably high affinity by other receptors, eg, ₂ARs and atypical ₁ARs, respectively. Finally, CEC, which has been widely applied to distinguish _1BARs from _1AARs, may give spurious results depending on the conditions used (for details see Reference 13¹³ ).

	Structure-Function Relationships

Top Introduction {alpha}1AR Subtypes Other Subtypes Evaluation of {alpha}AR Subtypes Structure-Function Relationships Intracellular Signaling and... Genomic Organization, Promoters,... 5' and 3' Untranslated... Regulation of... Summary References

 
₁ARs are members of the GPCR superfamily, which includes, at this time, several hundred distinct but related proteins.^{7 37} Like other members of this gene family, ₁ARs are single polypeptide chains, ranging from 429 to 561 amino acids in length. There is no evidence that the polypeptide chain is posttranslationally processed, although it is posttranslationally modified by the attachment of oligosaccharides (and probably fatty acids also) as well as phosphorylated. There is also no evidence for a clearly defined leader sequence, so membrane insertion most likely involves the use of cryptic signal sequences.

Each receptor contains seven stretches of 20 to 28 hydrophobic amino acids that likely represent membrane-spanning regions. In several instances, these hydrophobic stretches are interrupted by charged residues that are functionally important for ligand binding and signaling.³⁸ In this regard, the structure of ₁ARs is very similar to that of rhodopsin, the light-activated retinal receptor involved in visual transduction; bacteriorhodopsin, the light-activated proton pump of Halobacterium halobium, and ßARs.³⁸ However, there is little amino acid identity between ₁ARs and either rhodopsin or bacteriorhodopsin and only a low degree of identity (20% to 30%) with the ßAR, even though both ₁ARs and ßARs are activated by the catecholamines, epinephrine and norepinephrine.

The amino termini of ₁ARs are located extracellularly and contain several consensus sites for modification by N-linked glycosylation. Although glycosylation has only been demonstrated for the _1B subtype,³⁹ it is possible that at least the _1DAR is also glycosylated, since it migrates as a slightly larger species by SDS-PAGE than that predicted for the protein backbone (Table 3).⁴⁰ The amino termini vary considerably in length, with the terminus for the _1DAR being much longer (90 amino acids) than the terminus for the _1A/cAR (25 amino acids) or the _1BAR (42 amino acids) (Figure). This longer amino terminus of the a_1DAR may limit efficient translation or membrane insertion, since this subtype is more poorly expressed in the plasma membrane than the other two subtypes, despite abundant production of _1D mRNA.⁴⁰

View larger version (106K): [in this window] [in a new window]   Figure 1. Amino acid sequences of the cloned 1ARs. Identical residues are boxed. Colons indicate identity to the residue immediately above. Dashes indicate gaps that have been inserted to optimize alignments. Dots indicate that the residues at these positions have not been determined because of the availability of only partial cDNAs. Transmembrane-spanning regions (TMs) are indicated by the bold lines and were determined using the HRG algorithm.38

The carboxy termini are located intracellularly and contain consensus sites for phosphorylation by serine/threonine protein kinases, and modification of the proteins at these sites is involved in receptor desensitization.⁴ The carboxy terminal regions show little homology among the subtypes (Figure). However, these regions do contain a conserved cysteine residue, 16 amino acids after the end of the seventh transmembrane-spanning region that, like other GPCRs,⁴¹ is most likely posttranslationally modified by thioesterification with palmitic acid.

The transmembrane-spanning regions are linked by three intracellular and three extracellular loops. These loops, although variable, are each very similar in length among the subtypes. The first and second extracellular loops each contain a single cysteine residue, and analogous cysteines are highly conserved in all GPCRs. In the ßAR and in rhodopsin, these cysteine residues are essential for the correct folding of the proteins, for maturational glycosylation, and for expression in the plasma membrane. This is due to the involvement of these cysteines in a disulfide bond(s), although the disulfide linkage in the ß₂AR differs from that in other GPCRs.⁴² The _1BAR also has been shown to contain an essential disulfide bond, which is solvent inaccessible.⁴³ Like other members of the GPCR family, the second and third intracellular loops are likely to be involved in signaling through an interaction with receptor-coupled G proteins.^{44 45} In structure-function studies, Cotecchia et al⁴⁶ have demonstrated that 27 amino acids of the hamster _1BAR (residues 233 to 254), derived from the N-terminal portion of the third intracellular loop, are sufficient to allow activation of PI turnover in a chimeric ß₂/₁AR construct. Involvement of the third intracellular loop in receptor-mediated PI turnover has also been demonstrated in studies involving the cotransfection of both the _1BAR together with minigene constructs encoding various regions of this loop.⁴⁷ Interestingly, although a minigene construct encoding the entire third loop inhibited _1BAR-stimulated PI turnover, neither a construct encoding a region of the third loop that encompassed the 27–amino acid region, defined above, nor a construct encoding a 23–amino acid segment at the carboxy terminal end of the third loop was an effective inhibitor of PI turnover. However, coexpression of both the N- and C-terminal constructs was inhibitory to PI turnover. Thus, both of these regions of the third loop may be required for productive receptor–G-protein coupling, or physical interaction between these regions may be required to allow the formation of a conformation critical for receptor signaling. The inability of the C-terminal construct to inhibit receptor-stimulated PI turnover is also of interest, since point mutations in this region render the _1BAR constitutively active. In particular, mutation of Ala²⁹³ to any other amino acid results in a receptor that is constitutively active not only for PI turnover⁴⁸ but also for PLA₂-mediated arachidonic acid release.⁴⁹

The helical transmembrane regions of ₁ARs are most likely arranged in a bundle to form the binding pocket for the hydrophilic catecholamines. Like ßARs, binding of catecholamines and other adrenergic ligands by ₁ARs may involve an ion-pair interaction between a protonated amine of the ligands and the carboxylate side chain of a conserved aspartic acid (Asp¹²⁵ in the hamster _1BAR, equivalent to Asp¹¹³ in the hamster ß₂AR) in the third transmembrane segment. Interestingly, we have recently demonstrated that mutation of a cysteine residue (Cys¹²⁸), located one helical turn below Asp¹²⁵, to a phenylalanine also produces a receptor that is constitutively active.⁴⁹ However, by contrast with the Ala²⁹³ mutation, described above, this C128F mutant is constitutively active for PI turnover but not for PLA₂-mediated arachidonic acid release. This suggests that with activation of the wild-type receptor, agonists can induce isomerization of the receptor into at least two active conformations. By analogy with the ßAR, other residues that may participate in ligand binding include serines in the fifth transmembrane segment and a phenylalanine in the sixth transmembrane segment, which form hydrogen bonds with hydroxyl groups and a hydrophobic bond with the aromatic ring of adrenergic ligands, respectively.⁵⁰ With the ß₂AR, it has been postulated that hydrogen bonding of the two catechol hydroxyls of the natural phenethylamine agonists to the serine residues (Ser²⁰⁴ and Ser²⁰⁷) in the fifth transmembrane segment is required for full agonist activity. Thus, mutation of Ser²⁰⁴ to alanine decreases binding affinity by 10-fold and reduces intrinsic activity of full agonists. However, mutation of the corresponding residue (Ser²⁰⁸) in the hamster _1BAR does not alter receptor affinity for the natural catecholamine ligands.⁵¹ This suggests that in contrast to the ß₂AR, the determinants of agonist binding and receptor activation are not entirely conserved among other adrenergic receptors. Rather, with the _1BAR only hydrogen bonding between one hydroxyl and a single serine, most likely Ser²⁰⁷(equivalent to Ser²⁰⁴ in the ß₂AR), is involved in receptor activation.

Other residues involved in ligand binding have been identified recently from studies evaluating the determinants of subtype selectivity.⁵¹ These studies indicate that two of 172 amino acids in the transmembrane domains can almost entirely account for the differences in agonist recognition between the _1B- and _1A/c-receptor subtypes. Thus, mutation of both Ala²⁰⁴ in the fifth transmembrane segment and Leu³¹⁴ in the sixth transmembrane segment of the _1BAR to the corresponding residues (valine and methionine) in the _1A/cAR altered agonist binding from that observed with the wild-type _1BAR to that observed with the _1A/cAR. Further, reversal of these residues (Val¹⁸⁵ and Met²⁹³) in the _1A/cAR to those in the _1BAR resulted in a wild-type _1BAR agonist–binding profile. In addition to implicating these residues in both ligand binding and in subtype selectivity for agonists, which result from critical ligand-specific interactions (hydrophobic bonding with the phenyl ring and/or ortho substituents), these studies also indicate an important interaction between the side chains of these two residues.⁵¹

Further studies will be required to define the determinants of subtype selectivity for antagonists, as the binding of antagonists was not altered with either the _1B or _1A/c mutants described above. Given the lack of structural homology between various classes of ₁AR-specific antagonists, subtype selectivity for antagonists may be more complex and may involve overlapping but distinct sets of residues, as well as residues in the extracellular loops (M.-M. Zhao, J. Hwa, and D.M. Perez, unpublished data, 1996).

	Intracellular Signaling and Nuclear Pathways

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Stimulation of ₁ARs results in the activation of various effector enzymes, including PLC, PLA₂, and PLD, as well as activation of Ca²⁺ channels, Na⁺-H⁺ and Na⁺-Ca²⁺ exchange, and activation or inhibition of K⁺ channels. Additionally, ₁-receptor activation may lead to transcriptional activation of early- and late-response genes. In most cells, the primary functional response to activation of all ₁AR subtypes is an increase in intracellular Ca²⁺. Activation or inhibition of the receptor-coupled effectors involves coupling via guanine nucleotide–binding regulatory proteins (G proteins). Complexity of ₁AR signaling is due, in part, to the ability of the individual subtypes to couple to different effectors via distinct G proteins. In addition, the wide diversity of receptor-coupled effectors are tissue and species specific, and receptor, effector, and G-protein expression is developmentally regulated.

G Proteins
The G proteins coupling ₁ARs to their intracellular effectors and the selectivity of the various ₁AR subtypes for different G proteins have not been clearly defined. ₁ARs couple predominantly to pertussis toxin–insensitive G proteins of the G_q/11 family, and there is evidence for selectivity among the various ₁ subtypes for coupling to the different members of this family.⁵² For example, G_q, G₁₁, G₁₄, and G₁₆ can mediate phosphoinositol turnover by the _1BAR, but the _1DAR couples only via G_q or G₁₁.⁵² It has also been demonstrated in studies of intact tissue⁵³ and of the various cloned ₁ subtypes expressed in model eukaryotic expression systems⁵⁴ that the individual ₁ subtypes can activate multiple effectors via coupling to both pertussis toxin–sensitive (G_i or G_o family) and –insensitive G proteins. Moreover, both the and the ß subunits of the pertussis toxin–insensitive G proteins may mediate activation of certain receptor-coupled effectors, such as the ß isoform of PLC (PLCß).⁵⁵

In addition to activation of PLCß via G_q/11, there is recent evidence that the _1BAR activates a 69-kD PLC via coupling to a high molecular mass (74-kD) class of pertussis toxin–insensitive G proteins, termed G_h, that are distinct from the heterotrimeric G proteins.⁵⁶ These G_h proteins are multifunctional proteins with both transglutaminase and receptor signaling functions and are expressed in various tissues, including brain, heart, and liver.⁵⁶ Interestingly, binding of GTP by G_h inhibits its transglutaminase activity, whereas binding of Ca²⁺, which is required for transglutaminase activity, prevents GTP binding.

The selectivity of ₁AR coupling to PLC via G_q versus G_h remains to be defined, although there is recent evidence to suggest that the G_h system may mediate ₁AR-activated inositol bis-phosphate rather than inositol tris-phosphate production in intact myocardium⁵⁷ and Ca²⁺ mobilization in rat embryo brain cells.⁵⁸

Receptor-Coupled Effectors
₁AR-mediated activation of PLC results in the phosphodiesteratic cleavage of a minor component of the membrane phospholipid pool, phosphatidylinositol 4,5-diphosphate, to yield the second messengers, IP₃ and diacylglycerol. IP₃, thus generated, interacts with specific receptors on intracellular organelles, such as sarcoplasmic reticulum, to release stored Ca²⁺. Diacylglycerol activates PKC, which then phosphorylates a variety of cellular substrates, including Ca²⁺ channels, that may regulate intracellular Ca²⁺ or activate transcription of various genes (discussed below).

In addition to mobilizing Ca²⁺ from intracellular stores, activation of ₁ARs can increase extracellular Ca²⁺ entry via both voltage-dependent and -independent Ca²⁺ channels.^{5 59} Earlier, it was thought that these different pathways for increasing intracellular Ca²⁺ were subtype specific.⁵⁹ Thus, blockade of Ca²⁺ channels with dihydropyridines or removal of extracellular Ca²⁺ was found to inhibit _1A- but not _1B-mediated contractile responses in isolated vascular smooth muscle or Ca²⁺ influx in hepatocytes.⁵⁹ On the basis of such findings, it was suggested that _1AARs gate Ca²⁺ influx through voltage-dependent Ca²⁺ channels, whereas _1BARs mobilize intracellular Ca²⁺ via a PLC/IP₃ mechanism.⁵⁹ However, there are now numerous examples of exceptions to this subtype distinction in ₁AR-stimulated Ca²⁺ responses.

Although in most tissues activation of _1BARs increases Ca²⁺ mobilization via a PLC/IP₃ mechanism, in rat vena cava⁶⁰ and in MDCK-D1 cells⁵ _1BARs are linked to Ca²⁺ influx, although not through voltage-dependent Ca²⁺ channels. Also, although _1A-receptors can increase Ca²⁺ influx via G_q/11-regulated voltage-dependent Ca²⁺ channels, this subtype can also increase inositol phosphate formation.^{5 61}

Studies with expressed cloned ₁ subtypes demonstrate that all three subtypes can both mobilize intracellular Ca²⁺ and increase Ca²⁺ influx via voltage-operated Ca²⁺ channels.^{36 54} These studies also demonstrate that all three subtypes can couple not only to PLC activation but also to activation of PLA₂ and PLD and can promote cAMP accumulation.^{36 54} This latter effect probably occurs via a PKC-mediated potentiation of adenylyl cyclase activity,⁵⁴ although there is also evidence for ₁AR-mediated inhibition of cAMP degradation.⁶²

Control of cardiac function by ₁ARs and the signal transduction pathways involved have been reviewed recently¹ and thus will be considered here only briefly. In addition, the pathways involved have not been fully elucidated and remain controversial.^{63 64} Activation of PKC associated with cardiac ₁AR stimulation influences intracellular Ca²⁺ by inhibition of L-type Ca²⁺ channels or by activation of either Na⁺-Ca²⁺ exchange or the Na⁺-K⁺ pump. PKC also activates the Na⁺-H⁺ exchanger, which results in cytosolic alkalinization and increased contractility in ventricular myocytes and Purkinje fibers.¹ A number of cardiac K⁺ channels are either activated or suppressed by PKC. For example, ₁AR activation can either suppress the transient outward K⁺ current or activate the delayed rectifier K⁺ channel by a PKC-mediated mechanism.¹

In rat brain and tail artery, PKC can also activate PLD, which in turn cleaves phosphatidylcholine to yield the free polar head group of the phospholipid and phosphatidic acid. Stimulation of ₁ARs activates PKC via the second messenger, diacylglycerol, and also increases phosphatidic acid release. However, ₁AR-mediated PLD activation appears not to involve activation of PKC or Ca²⁺, since it is not blocked by PKC inhibitors or Ca²⁺ depletion.^{65 66}

Other Effectors and Nuclear Pathways
An active area of research is the involvement of ₁ARs in cell growth and hypertrophy. This has followed the seminal observation that in neonatal cardiomyocytes the hypertrophic response is not mediated by ßARs but is due to an exclusive ₁AR mechanism.⁶⁷ Thus, activation of myocyte ₁ARs increases protein synthesis as a result of increased transcriptional and translational activity. With ₁AR stimulation, there is an initial rapid induction (within 15 to 30 minutes) of a program of immediate-early gene expression, including c-fos, c-jun, c-myc, and Egr-1. At 12 to 24 hours, there is reactivation of a series of embryonic genes including atrial natriuretic factor, ß-myosin heavy chain, and skeletal -actin.⁶⁸ In vascular smooth muscle, ₁AR activation also causes a rapid (within 6 hours) increase in the expression of the growth-related genes, platelet-derived growth factor–A chain, and ornithine decarboxylase, without an increase in DNA synthesis.⁶⁹ After 24 to 48 hours of ₁AR activation, the expression of contractile protein genes, including myosin light chain-2 and cardiac -actin, is increased in cardiac myocytes and is associated with an increase in the number of contractile units.⁷⁰ This pattern of gene induction is specific for ₁AR activation and is distinct from that observed with ßAR stimulation or with thyroid hormone–induced hypertrophy.¹

The cellular pathways involved in these ₁AR-mediated responses are only beginning to be understood, but evidence is accumulating to implicate the _1A subtype and G_q and to link receptor activation to the growth factor pathway involving the protooncogene, ras, and its downstream kinases, Raf-1, mitogen-activated protein kinase kinase, mitogen-activated protein kinase, and S6 kinase.^{70 71} Activation of this cascade probably involves receptor-stimulated polyphosphoinositol turnover as well as activation of PKCß^{72 4} and a tyrosine kinase.⁷³ The nuclear pathways involved have not been completely elucidated, but a 9-bp "core" enhancer element corresponding to transcriptional enhancer factor-1 has recently been identified on the ß-myosin heavy chain promoter, and activation of this enhancer element is required for ß-myosin heavy chain induction by both ₁ARs and by the ß isoform of PKC.⁷⁴ Induction of skeletal -actin gene expression by ₁AR stimulation, on the other hand, involves both transcriptional enhancer factor-1 and a CArG box.⁷⁴ An increase in pH_i may also play a critical role in myocyte growth and may involve PKC-mediated activation of the Na⁺-H⁺ exchanger. However, there is also evidence for activation of a PKC-independent ₁AR response element in the induction of ANF gene expression that is associated with ₁AR stimulation.⁷⁵

	Genomic Organization, Promoters, and Regulatory Elements

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By contrast with the genes for many GPCRs, including those for the ß₁AR, ß₂AR, and the three ₂AR subtypes, which all lack introns, those for ₁ARs all contain a single intron.^{13 76 77} Thus, each of the genes for the three ₁AR subtypes consists of two exons and a single large intron (14 to 20 kb) that interrupts the coding region at the end of the putative sixth transmembrane domain. In all cases, the exon/intron boundary is situated after the first base of the codon, indicating a type-1 splice phase. This genomic organization is unique among those GPCR genes that do contain introns. These other genes contain four or more introns separating five or more exons, and the locations of the introns differ from those observed for ₁ARs.⁷⁶ However, like the intron in ₁AR genes, two of the four introns of the substance P gene are also very large (15 and 23 kb). Also, like ₁AR genes, the intron/exon boundaries and splice sites of those GPCRs that contain introns are reasonably conserved among receptor subtypes.⁷⁶ Southern blot analysis⁷⁶ and other data⁷⁸ indicate that the _1BAR is present as a single gene in the genome.

Given a genomic organization of two exons and only one intron, splicing of nascent transcripts cannot account for different ₁AR subtypes unless cryptic splice sites are used or unless there is transplicing of exons. Transplicing has, as yet, not been convincingly demonstrated for mammalian genes. However, there is evidence for the use of a cryptic splice site in transcription of the _1A/cAR.⁷⁹ This gives rise to two alternate splice variants, which differ in the length and sequences of their encoded C-terminal domains. In several tissues, the mRNA for both splice variants as well as the unspliced isoform were detected but were very low in abundance when compared with the unspliced variant. It is not yet clear whether these apparent low levels of transcription of the splice variants allow the expression of functionally significant amounts of receptor protein. Moreover, it remains to be determined whether the expression of these variant receptor isoforms contributes to the diversity of ₁AR signaling, since all three isoforms appear to have similar ligand- and PLC/Ca²⁺-signaling properties. By analogy with spliced and unspliced variants of the turkey ß₁AR,⁸⁰ it would be of interest if the different C-termini of the _1A/c variants also differentially regulated receptor endocytosis.

	5' and 3' Untranslated Regions

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The 5' and 3' untranslated regions of ₁AR genes have thus far only been evaluated in detail for the _1B subtype.^{76 78 81 82 83 84} The 5' flanking region (924 bp) of the human _1BAR gene contains neither a TATA box nor a CAAT box but is high in GC content (70%) and contains consensus sites for several Sp1 binding sites (GC boxes), consistent with promoters described for housekeeping genes, as well as a cAMP response element.⁷⁶

Primer extension studies and RNase protection assays indicated that several transcription start sites are used in various tissues, with a predominant site located 173 bp upstream from the translation start site.⁷⁶ The 3' untranslated region of the human _1BAR gene contains two putative polyadenylation signals. The first, starting 263 bp downstream from the stop codon, has one mismatch to the consensus AATAAA sequence. A second putative sequence, ATAAA, starting 492 bp downstream from the stop codon, also has one mismatch to the consensus sequence. It is likely that this second sequence is used, since analysis of a hamster _1BAR cDNA, which contains identical polyadenylation signals at the same locations after the stop codon, indicates that polyadenylation begins 14 bp after the second sequence.⁸⁵ This suggests that for both the hamster and human _1B transcripts, the 3' noncoding regions before the poly(A⁺) tails are 0.5 kb. Taken together, these findings predict that, excluding the poly(A⁺) tail, the mature _1BAR transcript is 2.2 kb, and by Northern blot analysis, a single transcript of 2.8 kb has been identified in various human tissues.⁷⁶

The 5' untranslated region of the rat _1BAR gene has also been sequenced and evaluated for transcriptional control elements.^{81 82 83 84} Like the human _1BAR gene, a cAMP response element has been identified in the rat gene.^{81 82} In the FRTL-5 cell line, activation of this cAMP response element by either TSH or dibutyryl cAMP increases both _1BAR transcription and expression of the receptor protein.⁸¹ The 5' untranslated region (1621 bp) of the rat _1BAR gene also has a high degree of similarity (87%) with the nucleotide sequence of the human gene located 500 bp upstream from the translation start site.⁸¹ Primer extension and RNase protection analyses using total RNA prepared from FRTL-5 cells indicated a single transcription start site located 173 bp upstream from the translation start site,⁸¹ corresponding to the major transcription start site identified for the human _1BAR gene.⁷⁶ Independently, Gao and Kunos⁸² have also found that the overall structure of the rat _1BAR gene is highly conserved with that of the human gene. They identified additional consensus sites for AP-1 and AP-2 binding sites and glucocorticoid and thyroid response elements in the 5' flanking region, as well as a putative polyadenylation signal (ATTAAA) at the same location in the 3' flanking region as in the human _1BAR gene. However, unlike the study of Kanasaki et al,⁸¹ who used FRTL-5 cells, Gao and Kunos,⁸³ who used poly(A⁺) RNA prepared from rat liver, initially identified two discrete transcription start points (tsp), located between -54 and -57 (tsp 1), and at -443 bp (tsp 2) upstream from the translation start site. Subsequently, they also reported the identification of an additional cluster of tsps between -1035 and -1340 bp, which contain a putative TATA and CAAT box and are flanked by several recognition sites for liver-specific transcription factors.⁸⁴ It was suggested that the use of these various tsps accounts for the identification of three _1BAR transcripts of 2.3, 2.7, and 3.3 kb, respectively, by Northern blot analyses of rat liver mRNA. Identification of two transcripts (2.7 and 3.3 kb) has also been reported for rat liver and brain by Cornett and colleagues,^{78 86} whereas only the 2.7-kb transcript was found in rat heart. Moreover, these investigators demonstrated that the differences in transcript sizes in rat liver are not likely to be due to differences in polyadenylation.

Very recently, Gao et al⁸⁴ have analyzed in detail the P2 promoter that results in transcription from tsp2 and presumably gives rise to the most abundant _1B transcript (2.7 kb) in rat liver as well as the single transcript (2.7 kb) in rat heart and various human tissues. By DNase I footprinting of rat liver extracts, three protected regions (-432 to -452, -490 to -540, and -609 to -690 bp) were identified in P2. Footprint II (-490 to -540 bp) contained four sites corresponding to half of an NF-1 consensus region. However, interestingly, this footprint binds two proteins distinct from NF-1: a ubiquitous CP-1–related factor and a novel factor. The latter, termed -ARTF, binds two adjacent GCTGG-containing sites in this region.⁸⁴ Deletion of either one of these -ARTF regions or of either the footprint I (-432 to -452 bp) or footprint II (-609 to -690 bp) regions abolished P2 promoter activity. Further, by DNA mobility shift assays, the -ARTF was demonstrated to be widely distributed in various tissues, but not in heart. Interestingly, the human _1BAR gene also has two GCTGG-containing regions in an identical location, although the 5' sequence has a single base (C for G) mismatch.⁷⁶ Failure to detect -ARTF in heart, despite the expression of a reasonably abundant 2.7-kb transcript, suggests that transcription in this tissue must be regulated by some alternative heart-specific factor(s); eg, consensus sequences for M-CAT and an E-box, which control cardiac-specific gene expression, are present in the rat gene.⁸⁴

The significance of transcription from three different _1BAR promoters in liver and brain, but not in heart, is unclear but may underlie developmental or tissue-specific regulation of the _1BAR. The use of multiple promoters separated by a large distance, which results in transcripts that encode the same protein, has been described previously.⁸⁴ In some instances, use of different promoters yields mRNAs with different AUG initiation codons, which, in turn, encode proteins with different amino termini. This is not the case with the human⁷⁶ or rat⁸³ _1BAR gene, since all upstream AUG codons are either not in-frame or are followed by stop codons. Moreover, unlike the genes for other GPCRs, neither the human nor rat _1BAR gene contains an intron in the 5' flanking region.

Although the gene for the _1A/cAR has been isolated,¹³ neither its regulatory elements nor those of the _1DAR gene have been defined. It is possible that transcription of these genes is also under the control of different promoters that are differentially activated in various tissues and species or in response to developmental or hormonal stimuli, since three _1A/c transcripts (5.0, 3.9, and 3.0 kb) and two _1D-transcripts (3.0 and 1.7 kb) have been identified in the human prostate with the use of cDNA probes that clearly do not cross-hybridize,⁸⁷ whereas only a single _1A/c and _1D transcript were observed in rat heart¹³ and in rat brain,^{15 16} respectively. Further studies will be required, however, to validate this possibility and to exclude cross hybridization with unrelated mRNA species or the use of alternate polyadenylation signals as the mechanism leading to the identification of different-sized transcripts for these ₁AR subtypes in some tissues.

It should be mentioned, in this regard, that analysis of ₁AR regulatory elements and transcripts is particularly problematic, since (1) the 5' flanking regions are very high in GC content, making primer extension, RNase protection, and PCR analyses of those regions difficult, (2) there is a high degree of homology between ₁AR subtypes, even at the nucleotide level, and (3) in many tissues, the abundance of ₁AR transcripts is extremely low. As a result, relatively large amounts of RNA are required for evaluation of ₁AR transcripts. This could potentially lead to the identification of unrelated cross-hybridizing species, which may account, in part, for some of the marked variations (eg, from 2.2 to 11 kb for the _1A/c, from 2.1 to 5.0 kb for the _1BAR, and from 1.7 to 3 kb for the _1DAR) in reported transcript sizes.^{15 16 36 87 88 89 90}

	Regulation of 1AR mRNA Levels

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Thus far, regulation of ₁AR gene expression at the transcriptional level has mainly been evaluated only for the _1B subtype. These studies indicate that _1BAR expression is highly regulated and, in some instances, occurs in an opposing direction in different tissues or cell lines and in response to development, aging, cellular differentiation, and various hormonal influences.

Regulation of _1BAR expression has been extensively evaluated in rat liver, where the effects of catecholamines are mediated both by Ca²⁺-mobilizing _1BARs and by cAMP-linked ß₂ARs. Although these adrenergic receptors couple to distinct signaling pathways and are the products of different genes, it has been well documented that in response to a variety of physiological and pathological conditions, their functional expression is reciprocally regulated.^{91 92} These studies indicate that in the intact organ of an adult animal, adrenergic activation of liver glycogenolysis is mediated by _1BARs. However, with perturbations that most likely result in dedifferentiation of hepatocytes, glycogenolysis is converted to a predominantly ß₂AR-mediated response. These conditions include dispersion of hepatocytes in primary culture, partial hepatectomy, cholestasis, malignant transformation of liver, hypothyroidism, and glucocorticoid deficiency.^{91 92}

In vitro incubation of hepatocytes isolated from adult male rats, for example, results in a decrease in _1BAR density, in the steady state levels of _1BAR mRNA, and in _1BAR-mediated phosphorylase activation and IP₃ accumulation, as well as in an increase in ß₂AR mRNA levels and ß₂AR-mediated cAMP accumulation.⁹¹ However, the degree of decrease in _1BAR expression with culture is inversely proportional to cell density, so that little decrease is observed when the density of cultured cells is high.⁹³ Also, with regeneration of the liver after an injury such as partial hepatectomy and presumably the restoration of cell-cell contacts, _1BAR expression is restored. These findings, plus the observation that _1BAR expression is developmentally regulated, with expression levels being low in fetal livers and increasing after birth until early adulthood,⁹⁴ indicate that _1BAR expression is a marker of cellular maturation or differentiation. In keeping with these observations, _1BAR expression decreases with aging, and in addition to the switch in adrenergic receptor expression and hepatic responsiveness to catecholamines that is observed with injury, hepatocytes reexpress other genes that are normally expressed only during fetal life.⁹² However, the mechanism underlying these alterations in hepatocyte gene regulation that result in the reexpression of the fetal phenotype remains largely unclear.

Interestingly, there is also a sexual dimorphism in hepatic AR responsiveness, with hepatocytes from adult female rats responding to both _1BAR and ß₂AR stimulation, whereas adult male hepatocytes respond only to _1BAR stimulation.⁹⁵

In contrast to the decrease in rat hepatocyte _1BAR expression observed with hypothyroidism, expression of _1BARs in this condition increases in rat heart and lung.³⁵ This indicates tissue-specific dimorphism in _1B gene regulation. Treatment with TSH, on the other hand, acting via the cAMP/A-kinase pathway, markedly increases _1BAR expression and functioning in both the FRTL-5 and PC Cl3 rat thyroid cell lines.^{81 96} An increase in _1BAR mRNA levels that is probably due to enhanced transcription has also been observed with cAMP activation in DDT1 MF2 smooth muscle cells.⁹⁷ In FRTL-5 cells, the effect of TSH is due to activation of a cAMP response element that increases _1B gene transcription and is associated with an increase in _1BAR mRNA abundance and with little change in mRNA degradation.⁸¹ In PC Cl3 cells, which express both _1A/c- and _1B-receptors, TSH increases _1BAR expression and _1B-mediated activation of Ca²⁺ influx. Although TSH-mediated activation of _1B-gene transcription was not evaluated in the study of Meucci et al,⁹⁶ the failure to see TSH-mediated changes in _1A/cAR provides at least circumstantial evidence to indicate that the regulation of ₁ARs is subtype specific, with only _1B transcription being cAMP dependent.

Transcripts for the _1BAR have been identified in the DDT1 MF2 hamster smooth muscle cell line and for the _1B and _1DAR but not _1A/cAR in rat vascular smooth muscle cells isolated from several vascular beds.^{98 99} In DDT1 MF2 cells, the glucocorticoid dexamethasone increases receptor density and the steady state levels of _1BAR mRNA, even in the presence of the protein synthesis inhibitor, cycloheximide.¹⁰⁰ _1BAR mRNA abundance is also increased in these cells by testosterone and aldosterone but not by ß-estradiol or progesterone. This dexamethasone-stimulated increase in _1BAR mRNA is due to an increased rate of _1B gene transcription, with no change in the half-life of _1BAR mRNA.¹⁰⁰ Increased transcription without change in mRNA stability has also been observed for the _1DAR in response to angiotensin II treatment of cultured rat aortic smooth muscle cells. This effect of angiotensin II was associated with increased ₁AR expression and _1DAR mRNA levels, as well as an increase in _1BAR mRNA, and involved a PKC-dependent, but Ca²⁺-independent, mechanism.⁹⁹ PKC-mediated activation of _1BAR gene transcription has also been observed in DDT1 MF2 cells.¹⁰¹ However, in rabbit aortic smooth muscle cells, activation of PKC as a result of _1BAR stimulation by norepinephrine, although having a permissive effect on _1BAR gene transcription, had a greater effect in destabilizing _1BAR mRNA.¹⁰² As a result, steady state _1BAR mRNA levels and receptor expression decreased. The persistent decrease in receptor expression, however, may involve additional mechanisms, since the decrease in _1BAR mRNA observed in the present study was only transient. Why PKC activation decreases _1BAR mRNA stability in aortic smooth muscle cells but not in DDT1 MF2 cells remains unclear. Since the PKC response in aortic smooth muscle cells is dependent on protein phosphorylation and can be prolonged by phosphatase inhibition by okadaic acid,¹⁰² the difference between these cells and DDT1 MF2 cells is probably due to either the expression of different PKC isoforms or to the differential expression of a critical PKC substrate in the two cell types.

Another interesting difference between rabbit aortic smooth muscle cells and DDT1 MF2 cells is the effect of cycloheximide on _1BAR expression. In the former cells, cycloheximide has been found to markedly prolong receptor half-life from 7 to 172 hours.¹⁰³ This effect has been interpreted to be due to cycloheximide-induced inhibition of the synthesis of a protein involved in receptor degradation. However, in the study of Izzo and Colucci,¹⁰³ the effects of cycloheximide on _1B gene transcription and mRNA stability or of other protein synthesis inhibitors on receptor half-life were not evaluated. By contrast, in DDT1 MF2 cells, cycloheximide increased _1BAR mRNA accumulation as a result of an increase in transcription, with no effect on mRNA stability.⁹⁰ Similar effects were also observed with the protein synthesis inhibitors anisomycin and emetine. However, activation of _1B gene transcription with these compounds was not due to a "superinduction" phenomenon, since a further inhibitor, puromycin, did not induce _1BAR mRNA, even at concentrations that completely inhibited protein synthesis.⁹⁰ Thus, in DDT1 MF2 cells, cycloheximide appears to be able to induce _1BAR gene expression through a direct effect on transcription.

	Summary

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Recent insights into ₁AR biology have confirmed the heterogeneity of this important class of signaling molecules and have identified enormous diversity in the signaling pathways used by ₁ARs in regulating cellular functions. Although initially confounding our understanding of ₁ARs, the molecular cloning of the various ₁ subtypes has clearly contributed greatly to these insights. Much remains to be learned, however, about the molecular mechanisms of receptor activation, the regulation of receptor expression, and the involvement of ₁ARs in physiology and disease. It is also of interest to speculate why there are multiple ₁ARs or, more generally, multiple subtypes of many members of the GPCR superfamily. For AR subtypes, this issue has been considered recently in an interesting commentary by Milligan et al.¹⁰⁴ This article, however, focused mainly on the possible reasons for having both - and ß-adrenergic receptors rather than on the implications of multiple ₁AR subtypes. With respect to the former, Milligan et al correctly point out that adrenergic control of cardiac function can no longer be considered to be exclusively by ß₁ARs, since ₁ARs, ₂ARs, ß₂ARs, and ß₃ARs have been identified on cardiac myocytes. ₁AR responses appear not to be as important in the normal heart as in disease states, where the heart is altered in favor of ₁ARs and ß₂ARs. This switch in adrenergic responsiveness may provide a backup for maintaining cardiac function in the event of ß₁AR failure. Thus, increased ₁ responsiveness is observed during chronic treatment with ß₁ antagonists in cardiac ischemia, cardiac hypertrophy, hypothyroidism, and diabetes.^{1 104} In blood vessels, AR and ßAR allow sympathetic control of both vascular smooth muscle contraction and dilation, respectively. ₁AR subtypes are present throughout the vasculature but are more prominent on the arterial side, where they regulate peripheral resistance. Venous tone, prejunctional modulation of sympathetic activity, and endothelial release of endothelium-derived relaxing factor, on the other hand, are mediated predominantly by ₂ARs.

With respect to the multiplicity of ₁AR subtypes, it is of interest that all three subtypes recognize the endogenous catecholamines norepinephrine and epinephrine with similar affinity, even though they can be distinguished by their differential binding of a variety of synthetic agonists and antagonists.⁵¹ This finding and the fact that all subtypes appear to activate all effector pathways similarly (note that thus far only activation of PLC, PLA₂, and PLD have been examined in detail for all subtypes) suggest that from the point of view of the organism, the various subtypes would be indistinguishable. Our ability to discriminate these subtypes may thus merely be due to the development of synthetic ligands that can detect subtle differences between their ligand recognition sites that are functionally inconsequential. If this hypothesis is correct, then it implies that teleologically the major functional consequences of the various subtypes lie not in their activation or signaling but in their ability to be differentially expressed during development (in response to various physiological or pathophysiological stimuli) and/or in various tissues and species. As a corollary, one can predict that the elements involved in the regulation of receptor gene expression will differ between the subtypes. From a pharmacological point of view, however, the potential for developing compounds that are highly selective for an individual subtype remains of considerable therapeutic significance.

	Selected Abbreviations and Acronyms

 

-ARTF = -adrenergic receptor transcription factor AR = adrenergic receptor CEC = chloroethylclonidine GPCR = G-protein–coupled receptor IP3 = inositol 1,4,5-tris-phosphate PCR = polymerase chain reaction PI = phosphatidylinositol PKC = protein kinase C PLA2, PLC, PLD = phospholipases A2, C, and D RT = reverse transcription TSH = thyroid-stimulating hormone

	Acknowledgments

 
This study was supported in part by funds from an Eccles Award and a project grant from the National Health and Medical Research Council, Australia; by National Institutes of Health grants NS-19583, HL-52544, and HL-38120; by a Grant-in-Aid from the American Heart Association; and by an educational grant from Glaxo, Inc. We are grateful to Elaine Martin for typing the manuscript and Dr S. Iismaa and Dr R.P. Riek for critical review of the manuscript. We also thank Dr David E. Clarke for providing unpublished data and both Dr Clarke and the reviewers for useful comments.

	Footnotes

 
Reprint requests to Dr R.M. Graham, Victor Chang Cardiac Research Institute, 376 Victoria St, Darlinghurst, NSW 2010, Australia.

¹ Where only a review is cited, original references are contained therein.

² As recommended by IUPHAR,¹⁴ lowercase subscripts are used to designate the cloned subtypes, and uppercase subscripts are used to designate the pharmacologically defined subtypes. When the pharmacologically defined correlate of cloned subtypes is established, only uppercase subscripts are then used.

This revised classification of ₁AR subtypes (Table 1) will be used throughout the remainder of this review.

³ Although the _1A designation has been recommended by IUPHAR,¹⁴ we prefer the _1A/c designation, since it encompasses reference to the initial designation of the cloned species, which should be helpful to readers unfamiliar with the history of ₁-subtype classification.

⁴ It should be noted that PKCß has not been uniformly detected in cardiac myocytes, and there is evidence that ₁ARs activate novel Ca²⁺-independent and not Ca²⁺-dependent PKC isoforms (see Reference 109¹⁰⁹ ).

Received July 27, 1995; accepted December 4, 1995.

	References

Top Introduction {alpha}1AR Subtypes Other Subtypes Evaluation of {alpha}AR Subtypes Structure-Function Relationships Intracellular Signaling and... Genomic Organization, Promoters,... 5' and 3' Untranslated... Regulation of... Summary References

 
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				F. Lin, W. A. Owens, S. Chen, M. E. Stevens, S. Kesteven, J. F. Arthur, E. A. Woodcock, M. P. Feneley, and R. M. Graham Targeted {alpha}1A-Adrenergic Receptor Overexpression Induces Enhanced Cardiac Contractility but not Hypertrophy Circ. Res., August 17, 2001; 89(4): 343 - 350. [Abstract] [Full Text] [PDF]

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