© 1999 American Heart Association, Inc.
Editorials |
A Novel Ca2+ Channel in Vascular Smooth Muscle?
From the Department of Physiology, University of Florida College of Medicine, Gainesville, Fla.
Correspondence to Dr Craig H. Gelband, Department of Physiology, University of Florida College of Medicine, PO Box 100274, Gainesville, FL 32610. E-mail Gelband{at}phys.med.ufl.edu
Key Words: arteriole • patch clamp • voltage-dependent Ca2+ channel • vascular tone
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Introduction |
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 Top Introduction References |
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Contraction of vascular smooth muscle cells (VSMCs) requires an increase in [Ca2+]i. This increase can occur via Ca2+ release from the sarcoplasmic reticulum or by influx of Ca2+ from the extracellular space through voltage-dependent Ca2+ channels (VDCCs) or receptor operated nonselective cation channels.1 A number of studies using dissociated or cultured VSMCs with origins from a range of vascular beds have demonstrated, using electrophysiological and molecular techniques, that a major contribution to Ca2+ influx in response to membrane depolarization and/or vasoactive agents is mediated via VDCCs. Two types of VDCCs have been recorded in VSMCs: L- and T-type. The L-type Ca2+ current is classified as high voltage activated (HVA) because it activates at membrane potentials at or more positive than -40 mV. The L-type class of VDCCs has a distinct pharmacology. L-type VDCCs are dihydropyridine (DHP) sensitive, and molecular cloning has confirmed that these channels contain unique domains on the pore-forming
subunit that confer this sensitivity. Because the
L-type VDCC is a major contributor to vascular tone, its unique
pharmacology has been exploited to treat cardiovascular
disorders such as hypertension.1 However, the ubiquitous
expression of L-type Ca2+ channels in many cell
types causes undesirable side effects when DHPs are clinically
used. Fewer published studies have shown that T-type Ca2+ current exists in smooth muscle cells.2 3 4 5 6 7 Unlike the HVA channels, electrophysiological data show that T-type Ca2+ current is DHP insensitive and activates at more negative membrane potentials. Additionally, T-type Ca2+ current inactivates whereas HVA channels show relatively little inactivation during a depolarizing voltage step. At first glance, this would seem a likely therapeutic target. However, the physiological role of this current component in VSMCs remains unclear. In fact, molecular evidence is needed in VSMCs to confirm that this current component is actually carried via T-type Ca2+ channels. In this issue of Circulation Research, Morita et al8 electrophysiologically define a DHP-insensitive VDCC with novel characteristics compared with previous Ca2+ current studies in VSMCs. Using the whole-cell patch-clamp technique, the authors find a significant majority of the Ca2+ current in VSMCs from mesenteric resistance arterioles of the guinea pig to be DHP insensitive. When VSMCs from more distal arterioles in the mesenteric vascular bed are examined, the DHP-insensitive current approached 100% of the total Ca2+ current. The extremely high expression is not paralleled by previous studies of non–L-type Ca2+ current in VSMCs. This study opens the possibility of a new therapeutic target for the management of vascular resistance.
A traditional interpretation of the data presented by Morita et
al8 may lead to the conclusion that the residual
Ca2+ current was T-type, as previously found in
other smooth muscle cell types, or R-type, which has not been found
previously in VSMCs. Perez-Reyes' group, in 1998 and 1999, has cloned
and characterized the subunits that underlie T-type
Ca2+ current: 1G,
1H, and
1I.9 10 11 Assigning a molecular
identity to these channels has shifted previous notions that
1E was the mediator of LVA
current12 13 and provides further evidence that
1E is the molecular equivalent of R-type
Ca2+ current. R-type Ca2+
current, so named because it is resistant to
antagonists used to identify other
Ca2+ channel subtypes, is predominantly neuronal
and activates at membrane potentials near -50 mV. Despite its
obviously distinct activation characteristics, R-type
Ca2+ current is classified as HVA current on the
basis of the sequence homology of the subunit compared with other
HVA channels and on other
electrophysiological characteristics that
are more like HVA channels. In fact, one could speculate that because
T- and R-type Ca2+ current are very similar in
their kinetic and pharmacological profiles, what was previously
characterized as T-type Ca2+ current in VSMCs
could indeed be a regulated R-type Ca2+ current
(ie, channel phosphorylation, ß subunit assembly, or
other protein-protein interactions).
Morita et al8 compare the characteristics of the DHP-insensitive current in guinea pig mesenteric arteriolar VSMCs with characteristics of both T- and R-type Ca2+ current. Although the activation parameters of the current in question are similar to those of R-type Ca2+ current, the inactivation parameters, particularly the time constant of inactivation, are strikingly similar to those of T-type Ca2+ current. Permeability analysis reveals that the DHP-insensitive current in this study is more similar to R-type Ca2+ current. However, pharmacological analysis of the current, according to traditional criteria such as nickel and cadmium sensitivity, does not clearly define it as R-type Ca2+ current. These conflicting data seem to make classification of this Ca2+ current as T-type or R-type unfeasible (see Table in Morita et al8 for further clarification).
Molecularly, Morita et al8 use RT-PCR in an attempt to
uncover the DHP-insensitive component of the Ca2+
current in RNA isolated from terminal mesenteric resistance arterioles
of guinea pig. Although 1C, the equivalent of
the DHP-sensitive current, mRNA is present,
1E cannot be amplified under the same
conditions that reveal 1E presence in mRNA
isolated from cerebellum. Despite the availability of the sequence for
T-type Ca2+ channels, Morita et al8
do not attempt to classify their current as LVA, and as such, do not
probe for its presence using RT-PCR. Regardless of this oversight, the
evidence presented in this study points to the possibility of a
novel Ca2+ channel with characteristics
overlapping both R-type and T-type current and perhaps bridges
the gap between LVA and HVA Ca2+ channel
families.
The relatively large expression of the DHP-insensitive current, approaching 100% of the total Ca2+ current in the mesenteric terminal arterioles, argues for a more significant role of non–L-type Ca2+ current in maintenance or alteration of vascular tone than has been suggested.1 However, before a ubiquitous role of this current is assigned, more arteriolar preparations from a number of different vascular beds must show both electrophysiological and molecular evidence of non–DHP-sensitive Ca2+ current. In fact, in VSMCs from a number of small arteriolar preparations, including those of the kidney, no DHP-insensitive Ca2+ current component is resolved.1 Given that the tone of small resistance arterioles contributes more significantly to alterations in blood pressure than does the tone of larger conduit vessels, perhaps the DHP-insensitive Ca2+ current, reported by Morita et al,8 is a more rational, more effective therapeutic target than L-type Ca2+ current. A novel Ca2+ current type, or even R-type Ca2+ current, in these vessels would be an exciting target for clinical agents without many of the cardiovascular side effects.
The findings presented by Morita et al8 fuel curiosity regarding the molecular identity of the Ca2+ currents in resistance arterioles, which hopefully will be elucidated in the near future. If the current is indeed carried via a novel Ca2+ channel subtype, structural analysis of this channel compared with the HVA and LVA families is likely to reveal nonconserved gating regions that can be exploited for rational drug design for the treatment of cardiovascular diseases. Data presented in Morita et al8 will no doubt spark interest in the molecular identity of the DHP-insensitive Ca2+ current component in mesenteric resistance arterioles, not only for potential therapeutic value but also for reinvestigation of former dogma regarding the role of non–L-type Ca2+ current in vascular smooth muscle cells.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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