© 1999 American Heart Association, Inc.
Original Contribution |
Acid-Evoked Currents in Cardiac Sensory Neurons
A Possible Mediator of Myocardial Ischemic Sensation
From the Vollum Institute (C.J.B., S.P.E, E.W.M.) and Division of Cardiology (C.J.B.), Oregon Health Sciences University, Portland, Ore.
Correspondence to Christopher J. Benson, Division of Cardiology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, UHN-62, Portland, OR 97201-3098. E-mail bensonc{at}ohsu.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—Sensory neurons that innervate the heart sense ischemia and mediate angina. To use patch-clamp methods to study ion channels on these cells, we fluorescently labeled cardiac sensory neurons (CSNs) in rats so that they could later be identified in dissociated primary culture of either nodose or dorsal root ganglia (DRG). Currents evoked by a variety of different agonists imply the importance of lowered pH (
7.0) in signaling ischemia. Acidic pH evoked extremely large
depolarizing current in almost all cardiac afferent neurons from the
DRG (CDRGNs). In contrast, only about half of the unlabeled DRG neurons
responded to acid, and their current amplitudes were much less than
that in CDRGNs. In all respects tested—kinetics, selectivity, and
pharmacology—the acid-evoked current was similar to that of previously
described native and cloned acid-sensing ion channels. Cardiac
afferents from the nodose ganglia differed from CDRGNs in having
smaller acid-evoked currents but clearly larger currents evoked by ATP.
Serotonin, acetylcholine, bradykinin, and adenosine
elicited currents in fewer CSNs than did ATP or lowered pH, and the
currents were relatively small. Capsaicin, an activator of
small nociceptive sensory neurons that innervate skin, evoked
only small and rare currents in CDRGNs. The extremely large amplitude
and prevalent expression of acid-evoked current in CSNs imply a
critical role for acidity in sensation associated with myocardial
ischemia.
Key Words: myocardial ischemia • cardiac sensory neuron • proton • whole-cell patch clamp
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Although much is understood about the effect of autonomic nervous system input to the heart, the cardiac sensory, or afferent, system and its role in physiological and pathological conditions are less well understood. Historically, the major impetus for research on the cardiac sensory system has been to find the source of cardiac pain, or angina. During the first half of this century, the neuroanatomical pathways of the cardiac sensory system were defined by clinical reports of surgical attempts to relieve angina and by experimental studies.1 2 These studies revealed that the cardiac sensory neurons (CSNs) follow the sympathetic and vagal nerve tracts en route to the central nervous system (Figure 1
). The cell bodies of those sensory
axons following the sympathetic tracts are found in the upper thoracic
dorsal root ganglia (DRG); those following the vagal tracts are located
in the nodose ganglia. The sensory innervation of the fibrous and
serous parietal pericardium, separate from that of the heart and
epicardium, follows the phrenic nerves to the cervical DRG
(C3-C5).3 4
|
It has long been understood that cardiac pain is associated with myocardial ischemia, which causes oxygen supply/demand insufficiency.5 In various whole-animal preparations, occlusion of a coronary artery activates the cardiac afferent nerve fibers in the sympathetic6 7 8 and vagal tracts.9 10 Various substances released during myocardial ischemia have been implicated as chemical mediators of myocardial ischemic sensation. Several of these substances have been shown to activate CSNs: ATP,8 10 serotonin (5HT),11 bradykinin (BK),12 13 and adenosine.8 10 In turn, stimulation of sensory fibers elicits reflexes specifically mediated by the sympathetic tract14 and by the vagal tract.15 Still, the precise stimuli that are sensed during myocardial ischemia are incompletely understood (see Reference 1616 for review).
A likely contributor is acid. The heart is an organ of high metabolic activity and is susceptible to drops in pH during ischemia or hypoxia. It has been demonstrated that pH is lowered intracellularly17 and extracellularly18 19 in ischemic heart models and clinically in patients with coronary artery disease.20 In dogs, lowered pH stimulates afferent cardiac sympathetic nerve fibers.21 In another organ system, rat skin, acid plays a dominant role in exciting sensory neurons when compared with other potential chemical mediators of inflammation.22
Acid evokes depolarizing currents in sensory neurons studied in primary dissociated culture,23 24 25 26 and a variety of different components are distinguished by kinetic criteria.27 Most components activate somewhere between pH 7 and pH 6 and desensitize in response to a maintained stimulus. These desensitizing currents all have the unusual property of selectively passing Na+ over K+ about as effectively as voltage-gated Na+ channels. In addition to the desensitizing, Na+-selective currents in DRG neurons, there is a sustained, nonselective current that is evoked by pH below 6.0.26 The channels underlying these currents are believed to be the recently cloned acid-sensing ion channels (ASICs), which are members of the amiloride-sensitive Na+ channel/degenerin family of cation channels.28
These acid-evoked currents may play a role in mediating the pain of cardiac and skeletal muscle ischemia and perhaps also of inflammation. It is difficult to explore this possibility in culture, because the sensory modality and the site of innervation of individual neurons are not known. The first goal of the present study was to fluorescently label CSNs in the rat so that they can later be distinguished from other sensory neurons in dissociated culture; we accomplished this using a retrogradely transported dye placed in the pericardial space. We found that acid evoked extraordinarily large currents in the cardiac afferent neurons from the DRG (CDRGNs) compared with other, unlabeled DRG neurons (UDRGNs). The very high expression of these currents in cells thought to be specialized for sensing ischemia suggests an important role of acid in mediating cardiac pain.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In Vivo Labeling of CSNs
Surgical Preparation
Sprague-Dawley rats (200 to 300 g) were anesthetized by intramuscular injection of 1 mL/kg rat anesthetic (in mg/mL, ketamine 55, xylazine 5.5, and acepromazine 1.1). Each animal was intubated and respiration maintained with a rodent ventilator (Harvard model 683). The heart and thymus were exposed through a left lateral thoracotomy at the fifth intercostal space. The thymus, with the anterior superior portion of the pericardium adherent to its undersurface, was gently retracted cephalad to better delineate the pericardium and pericardial space. Twenty-five microliters of a suspension of 17 mg/mL of 1,1'-dioctadecyl-3,3',3'-tetramethyl indocarbocyanine perchlorate (DiI; Molecular Probes) in saline solution was injected into the pericardial space. The rat pericardial membrane is thin and contains microscopic pores29 ; thus, a suspension rather than solution of the lipophilic DiI was used to decrease the potential of leakage of dye from the pericardial space. After injection, the ribs were approximated, the thoracic cavity was evacuated, and the incision was closed in layers. The animals were cared for in accordance with the current Guide for the Care and Use of Laboratory Animals (US Public Health Service, Department of Health and Human Services) and guidelines of the Institutional Animal Care and Use Committee of Oregon Health Sciences University.
Tissue Culture and Identification of Labeled CSNs
During the 2- to 4-week postoperative period, DiI was carried
through retrograde transport back to the cell bodies of the CSNs. The
rats were then sacrificed, and the right and left dorsal root
(C8-T3) and nodose ganglia
were collected. The ganglia were dissociated and cultured as previously
described, except that the Percoll spin was omitted.30 In
brief, the ganglia underwent enzymatic dissociation successively in
papain and collagenase/dispase solutions; this was followed
by trituration in Hanks solution. The cells were then plated on
polylysine- and laminin-coated plastic in F12 medium plus nerve growth
factor (50 ng/mL) at 37°C in 5% CO2. After
several hours, the medium was changed to L15 plus nerve growth factor,
and the cells were maintained at 22°C in air. CSNs were identified by
fluorescence microscopy (Figure 2C and 2D). From the animals that
underwent the pericardial space injection preparation, the following 3
populations of sensory neurons were obtained for study: (1) labeled
CDRGNs, (2) UDRGNs, and (3) labeled neurons from the nodose ganglia
(CNodNs).
|
Control Experiments
To check for dye leakage from the pericardium and to explore the
effects of labeling at different injection sites, we performed several
control procedures. First, after a pericardial space injection, the
heart and lungs were sectioned at the time of euthanization and viewed
under a fluorescence microscope. Whereas the heart
consistently displayed confluent fluorescence over the
epicardium (Figure 2A
and 2B), the surface of the lungs
contained only an occasional isolated crystal of dye. Next, to test
whether dye leakage from the pericardial space would cause significant
contamination, we intentionally injected dye in the following sites in
separate animals: the left pleural space, the left
ventricular chamber, or the right ventricular
chamber. As expected, sectioning of the lungs after injecting into the
right ventricular chamber revealed confluent
pulmonary vascular embolization of the dye. Next, in an effort
to label sensory nerve terminals deeper within the
myocardium, we stabilized the heart with sutures and made
several intramural injections into the left ventricular
myocardium (Figure 2E and 2F).
The numbers of labeled sensory neurons obtained in culture of the DRG
after the various injection experiments are listed in the
Table. The pericardial space injection
resulted in a significantly greater number of labeled neurons in the
DRG than the various control injection site experiments. Thus, despite
the potential for dye leakage from the pericardial space, it would
cause little contamination because relatively few cells were labeled
with intentional injection into the pleural space. Because of the low
number of neurons labeled by the intramural injections, we abandoned
this experimental preparation. The number of nodose ganglion neurons
labeled by the pericardial space injection was not quantified; however,
there appeared to be a higher fraction of labeled cells in the nodose
ganglion (
10%) than in the DRG (1%) cultures.
|
Whole-Cell Patch-Clamp Recording
Whole-cell currents were recorded with an EPC-9 amplifier
(HEKA Elektronik). For most experiments, pipettes of 2- to 4-M
resistance were filled with KCl internal solution containing (in
mmol/L) KCl 100, EGTA 10, HEPES 40, MgCl2 5,
Na2ATP 2, and Na3GTP 0.3,
adjusted to pH 7.4 with KOH unless otherwise stated. For the monovalent
permeability experiments, NaCl replaced KCl in the internal solution,
and pH was adjusted with NaOH; high internal Na+
eliminated contamination by large, outward K+
currents. For the Ca2+ permeability experiments,
the internal solution consisted of (in mmol/L)
N-methyl glucamine 90 (titrated with HCl), NaCl 10,
EGTA 10, HEPES 40, MgCl2 5,
Na2ATP 2, and Na3GTP 0.3,
pH adjusted with tetramethylammonium (TMA)-OH. Our strategy was to
measure relative Na+ and
Ca2+ permeability by using similar
Na+ and Ca2+ activities
inside and outside the cell, respectively. Standard extracellular
solutions contained (in mmol/L) NaCl 130, KCl 5,
CaCl2 2, MgCl2 1, HEPES 10,
and MES 10, pH adjusted with TMA-OH. TMA-Cl was added to the various pH
solutions to equalize the concentration of TMA. For the monovalent
permeability experiments, the extracellular solutions consisted of
(in mmol/L) NaCl (or KCl, NaCH3SO3,
or CsCl) 130, CaCl2 2,
MgCl2 1, HEPES 10, and MES 10; pH was adjusted
with NaOH, KOH, or CsOH. For the Ca2+
permeability experiments, external solutions consisted of (in
mmol/L) N-methyl glucamine 120 (titrated with HCl),
HEPES 10, MES 10, and CaCl2 10 or 30. For
experiments on Ca2+ block, external solutions
consisted of (in mmol/L) NaCl 130; HEPES 10; MES 10; and
CaCl2 1, 2, or 10. The series resistance ranged
from 3 to 7 M, and it was compensated by 50%.
All dose-response curves were made by random-order application of
various concentrations at 30-second intervals. Solutions were applied
through an array of 1- or 10-µL pipes positioned 50 µm from
the cell under 40 cm of water pressure. Rapid solution exchanges were
controlled via computer-driven solenoid valves and were accomplished
within 5 ms as measured by an osmotically induced change in current
(Figure 5A). Cells were held at –70 mV unless otherwise stated.
Experiments were performed at room temperature (22°C). We studied
most cells after 1 to 2 days in culture; however, some experiments were
done on cells cultured up to 7 days. We saw no obvious difference in
the responses of cells cultured for longer times.
|
) than the
slow transient (
) current. Time constants for activation and
desensitization at various pH solutions are from exponential fits to
the rising and falling phase of currents, as in panels A and B.
Recovery times are at pH 7.4. Horizontal axis indicates interval at pH
7.4 spent between 2 pulses to pH 6.8. The first pulse completely
desensitizes the current, and the second tests the extent of recovery.
Vertical axis is the relative amplitude of currents evoked by the
second and first pulses. Time constants of the exponential fits are
0.44 and 6.8 seconds for the fast and slow currents,
respectively.
Data Analysis
The equation
I(H+)=1/{1+(K0.5/[H+])n},
where pH at half-maximal response is –log
K0.5, and I is the current at a
given proton concentration, [H+], was best-fit to the
dose-response data using the program NFIT (University of Texas Medical
Branch, Galveston, TX), a least-squares algorithm. PulseFit (HEKA
Elektronik) was used to determine the time constants of current
activation and desensitization, fit to a single exponential. Igor
software (WaveMetrics, Inc) was used to curve-fit the time of recovery
from desensitization. Permeability ratios were calculated from reversal
potentials using the Goldman-Hodgkin-Katz equation.31
PNa:PK was
calculated from the change in reversal potential (
Erev)
when K+ replaced Na+ in the
external solution:
Erev=(RT/F)ln{PNa+[Na+]o/PK+[K+]o},
where T is absolute temperature, R and
F are gas and Faraday constants, respectively, and brackets
indicate concentrations.
PNa:PCa was
calculated from the absolute reversal potential with
Na+ and Ca2+ as the only
current carriers inside and outside the cell, respectively, using the
following equation:
Erev=(RT/2F)ln{4PCa2+[Ca2+]o/PNa+[Na+]i}.
Data are reported as mean±SEM. Statistical analysis was
performed with an unpaired t test. A value of
P<0.01 was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Response of CSNs to Chemical Stimuli
To study the response of CSNs to potential chemical mediators of ischemia, the following chemicals were each dissolved in an external solution of pH 7.4: in µmol/L, ATP 30,32 5HT 30,33 capsaicin 1,34 acetylcholine (ACh) 200,35 and adenosine 200,37 as well as 500 nmol/L BK.36 The concentrations chosen for each compound produced maximal responses in our experiments and in the references cited. The largest measured currents (8.58±1.44 nA) were consistently evoked (93%) by acid applied to CDRGNs (Figure 3
). A smaller percentage of UDRGNs (54%)
and CNodNs (74%) responded to acid, and the cells that responded
displayed significantly smaller currents (3.48±1.10 nA in UDRGNs and
1.15±0.23 nA in CNodNs; P<0.01 versus pH-evoked current in
CDRGNs) (Figure 3B and 3C). These differences between cell
populations refer to the amplitude of transient acid-evoked current
(see below); the sustained component evoked by very low pH was seen in
virtually every neuron and did not distinguish different cell
populations.
|
Another consistent and large response (4.87±0.59 nA) was
evoked by ATP acting on ion channels called P2X receptors in CNodNs.
The current was slow activating and only partially desensitized (data
not shown), which is indicative of the heteromeric combination of
P2X2 and P2X3 receptor subtypes previously described in nodose
neurons.38 In contrast, the ATP-evoked currents in CDRGNs
and UDRGNs were substantially smaller and consisted primarily of a
fast-activating and fast-desensitizing current (Figure 3A),
which suggests either the P2X1 or P2X3 receptor
subtypes.39 CSNs sometimes responded to the other
chemicals indicated in Figure 3; however, they did so
inconsistently, and the amplitude of evoked currents in the
responders was much smaller than with either pH or ATP (Figure 3B and 3C).
Biophysical and Pharmacological Properties of Acid-Evoked Currents
in CDRGNs
The exceptionally large amplitude and prevalence of the transient
acid-evoked current in CDRGNs suggests its significance in sensing
cardiac ischemia. Therefore, we characterized its biophysical
and pharmacological properties to see how these compared with the
variety of acid-evoked currents seen in sensory
neurons.23 24 25 26 In short, we found no properties unexpected
from those described in the literature.
A drop in pH to 7.0 reproducibly evoked a transient, rapidly activating
and rapidly desensitizing current in CDRGNs (Figure 4A and 4C). This transient current was
half-activated by a pH step to 6.6 and half-desensitized by
preincubation at pH 7.2 (Figure 4C). The Hill coefficient of the
activation curve was 2.5. A smaller, nondesensitizing current was
evoked by more extreme decreases in pH (6). The activation curve for
this current is fitted with a pH0.5 of 3.7. The
combination of transient and sustained components at low pH has
previously been seen in unlabeled rat sensory
neurons.26 27
|
, n=6) currents.
Varying the pH before a test stimulus of pH 5 revealed that a
significant fraction of the transient current is desensitized at a
resting pH of 7.4 (Figure 4B). This is consistent with
the previous demonstration that acid-evoked channels need not open to
desensitize.25 The steady-state desensitization and
activation curves show clear overlap in the vicinity of pH 7 (Figure 7C and inset), suggesting that the channel can generate a
standing current at pH 7.
|
A closer look at the time constants of activation and desensitization
of the transient currents in CDRGNs revealed multiple transient
components (Figure 5), as noted by
Krishtal and Pidoplichko.27 Most cells exhibited a
rapidly activating and desensitizing current, but some had a current
that was 10-fold slower. The fast and slow transient currents were not
exclusive; a few neurons displayed both currents, which was evident as
biphasic activation and/or desensitization. These cells were not
included in the analysis of time constants. The rate of
recovery from desensitization differed for the fast and slow transient
currents in CDRGNs (Figure 5C). In a control solution of pH 7.4,
the fast transient current recovered with 
=0.44 seconds, and the
slow transient current recovered with =6.8 seconds.
The fast transient current is Na+ selective but
Ca2+ permeable (Figure 6). With the usual internal (high
K+) and external (high Na+)
solutions, the reversal potential was in the vicinity of +50 mV (data
not shown). To quantify the evident preference for
Na+ over K+, we measured
reversal potentials with Na+ as the internal ion
(see Materials and Methods). The reversal potential shifted –50±1.2
mV when K+ replaced Na+,
corresponding to a
PNa/PK of
6.8.
|
Current-voltage relationships measured in 10 mmol/L extracellular
Ca2+ with 15 mmol/L intracellular
Na+ displayed an average reversal potential of
–47.2±1.2 mV (n=7), corresponding to a
PNa/PCa of 105
(Figure 6C). In all cells, current amplitude increased when
[Ca2+] was increased from 10 to 30 mmol/L
(n=7; amplitude increase varied from 28% to 725%; data not shown).
Thus, as previously shown,40 the current can be
carried by Ca2+. To determine whether the
acid-evoked currents are blocked by millimolar extracellular
Ca2+, as seen in some native24 25
and cloned41 channels, we measured
Na+ currents elicited by pH 6.0 in 1, 2, and
10 mmol/L Ca2+. There was no change in
amplitude (n=5; data not shown); therefore, the current was not blocked
by millimolar Ca2+ concentrations.
The fast transient and sustained current components differ in 2
respects: ion selectivity (Figure 7A) and
pharmacology (Figure 7B). Both components are cation selective,
because they were unchanged when extracellular
Cl– was replaced with the impermeant anion
CH3SO3-. Replacement
of extracellular Na+ with
Cs+ revealed that the transient current does not
readily pass Cs+, whereas the sustained current
does. Thus, as previously described in UDRGNs,26 the
transient current is selective for Na+, whereas
the sustained current is a nonselective cationic current.
Amiloride, a K+-sparing diuretic that has
been shown to block proton-activated currents in mouse
neuroblastoma cells,42 blocked the fast transient current
(IC50=9.2 µmol/L) but not the sustained
current (Figure 7B). This difference is consistent with
one of the ASICs.43 The slow transient current was
similarly inhibited by amiloride (data not shown). The amiloride
derivative ethylisopropylamiloride inhibited the fast transient current
with an IC50 of 37.6 µmol/L (data not
shown). These blocking concentrations are 100-fold greater than
those needed to block the epithelial amiloride-sensitive
Na+ channel44 and are high enough to
block unrelated ion channels.42
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
There are 4 key findings in this study, as follows. (1) We describe a method to distinguish CSNs from neurons of other sensory modalities in primary dissociated tissue culture. (2) Compared with other sensory neurons, CDRGNs have extremely large currents evoked when pH drops to 7.0 or below. (3) CNodNs have smaller acid-evoked currents, but larger ATP-evoked currents than CDRGNs. (4) Other than its large amplitude, the acid-evoked current in CSNs has no biophysical or pharmacological properties that are not predicted by previous studies of acid-evoked currents in sensory neurons. The large amplitude indicates the importance of acid in mediating pain due to cardiac ischemia, but it certainly does not imply that other potential mediators are unimportant.
Isolation of CSNs
As described in Materials and Methods, considerable effort was
made to validate this preparation. Each of the control injection
experiments resulted in significantly fewer labeled neurons compared
with the pericardial space injections; this lends support to our
assertion that we have specifically labeled and isolated CSNs. Finally,
the different responses between the labeled DRG neurons and UDRGNs in
our whole-cell patch-clamp experiments provide further evidence that we
have isolated a distinct subgroup of sensory neurons from the DRG
population at large.
Although neuroanatomy was not the primary focus of this study, some anatomical information can be gleaned from our data. The number of labeled neurons we obtained was consistent with previous neuroanatomical studies in the rat in which fluorescent tracers were injected into the pericardial space.4 45 In contrast to the large number of labeled neurons appearing after pericardial space injections, we found relatively few labeled neurons after intramural injections. This may reflect either less tissue exposure to dye compared with the pericardial space injection or a true paucity of nerve terminals within the rat intramural myocardium. The endocardial layers were not labeled in our study. Interestingly, in a dog preparation, myocardial ischemia caused cardiac sympathetic afferent firing only if the ischemia was transmural and involved the superficial epicardial layers.10
Chemical Activation of CSNs
Several insights arise from a comparison of responses to different
agonists in the different cell populations that we isolated. Most
importantly, modest decreases in extracellular pH (ie, to pH 7.0 or
below) evoke exceptionally large currents in almost all epicardial
CDRGNs. In contrast, and as reported previously,26 27 only
50% of UDRGNs respond to acid; those that did respond had much
smaller average currents than CDRGNs.46
Cardiac afferents with cell bodies in the DRG differed from those in the nodose ganglia. CNodNs had significantly smaller acid-evoked currents and larger ATP-evoked currents than CDRGNs. This raises the possibility that the 2 cell populations sense different chemical signals during cardiac ischemia.
There are 2 classes of molecules that are proposed to sense changes in extracellular pH in sensory neurons: ASICs and vanilloid (capsaicin) receptors. Vanilloid receptors are activated by noxious heat and by capsaicin (the compound in pepper that tastes "hot"); also, current through vanilloid receptors is strongly increased by acidic pH.34 47 Therefore, it is considered that vanilloid receptors, in addition to sensing heat, may mediate sensory responses to acidity caused by inflammation and ischemia. The neurons we isolated detect cardiac ischemia, yet only a small fraction exhibit capsaicin-activated current, and those that do respond have small currents compared with UDRGNs. In contrast, almost all exhibit grossly large currents through ASICs. These results argue that ASICs are more important than vanilloid receptors for sensing myocardial ischemia.
5HT evoked currents that were substantial in cardiac afferents, but they were still smaller than the acid- or ATP-evoked currents. Various cells that contribute to the immune response to tissue damage release 5HT, so these currents may provide a means of communication between immune cells and CSNs.
Of the chemicals tested, protons, ATP, 5HT, and capsaicin activate ion channels (the ASICs,28 P2X receptors,38 39 5HT3 receptor,33 and vanilloid receptors,34 respectively) that are presumed to serve as sensory transducers in sensory neurons. No current was ever evoked by ACh, but currents were occasionally seen in response to BK or adenosine. We do not infer anything from the relatively rare and small currents evoked by these compounds, because they do not directly gate ion channels in sensory neurons; in fact, adenosine inhibits a Ca2+-activated K+ channel.37 The current we saw presumably arose from modulation of a channel by an intracellular signaling cascade; the importance of this may be understated by simply comparing the amplitude with those of channels directly gated by protons, ATP, or 5HT.
Physiological and Pathophysiological
Significance
CSNs respond to lowered pH (in the range produced by myocardial
ischemia) with consistent and robust depolarizing
currents; this suggests that acid is a potential mediator of myocardial
ischemic sensation.
In humans, the only conscious sensation from the heart is pain or angina, which most commonly occurs during myocardial ischemia. However, objective measurements of myocardial ischemia often do not correlate with the presence or severity of chest pain. In fact, ambulatory electrocardiographic monitoring in patients with myocardial ischemia has revealed that the majority of ischemic episodes are not reported as painful.48 Attempts to model ischemic cardiac pain in animals have produced variable results. The pseudoaffective measures of pain in these behavioral studies correlate poorly with sensory neuronal activation.13 16 49 Thus, it is reasonable to conclude that activation of CSNs with acid does not equate with nociception. For example, in patients with "silent" ischemia (defined as objective myocardial ischemia that is painless), there is evidence of sensory activation to the level of the thalamus, whereas patients with typical angina have additional activation of the cerebral cortex.50 Thus, the conscious perception of chest pain most certainly involves complex central processing and integration at multiple levels, and activation of CSNs is probably necessary but not sufficient to produce pain. Regardless, ischemia- or acid-induced activation of CSNs, whether painful or not, may be an important initiator of cardiovascular reflexes in pathological cardiac conditions.
A broad range of cardiovascular disease processes, including myocardial ischemia,51 congestive heart failure,52 and arrhythmias,53 are precipitated or worsened by perturbations in the autonomic nervous system. Much of the current pharmacological therapies are directed toward blocking the compensatory, but often deleterious, neurohormonal systems that are activated in these diseases. In human skeletal muscle, ischemia-induced acidic pH is coupled with sympathetic efferent nerve discharge.54 Also, abdominal visceral ischemia leads to profound cardiovascular reflex changes, the degree of which appears related to the level of the resulting acidosis.55 A similar acid-evoked reflex loop may exist in the heart and contribute to the detrimental effect of sympathetic activation in myocardial ischemic conditions. Specific blockade of acid-evoked activation of CSNs presents a potential new therapeutic management strategy in the treatment of ischemic heart disease.
|
Acknowledgments |
|---|
This study was supported by the following NIH grants: RO1DAO7415, Cardiovascular Signaling Training Grant T32-HL07817 (to C.J.B.), and Neuronal Signal Transduction Training Grant NS07381 (to S.P.E.). We thank G. Giraud and K. Thornburg for their comments on the manuscript and V.C. Dang for technical assistance.
Received August 12, 1998; accepted February 10, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Cutler EC. Summary of experiences up-to-date in the surgical treatment of angina pectoris. Am J Med Sci. 1927;173:613–624.
2. White JC. Cardiac pain: anatomic pathways and physiologic mechanisms. Circulation. 1957;16:644–655.[Medline] [Order article via Infotrieve]
3. Berry M, Bannister LH, Standering SM, eds. Gray's Anatomy. New York, NY: Churchill Livingstone; 1995;901–1397.
4. McNeill DL, Burden HW. Convergence of sensory processes from the heart and left ulnar nerve onto a single afferent perikaryon: a neuroanatomical study in the rat employing fluorescent tracers. Anat Rec. 1986;214:441–444.[Medline] [Order article via Infotrieve]
5.
Lewis T. Pain in muscular ischemia: its
relation to anginal pain. Arch Int Med. 1932;49:713–727.
6.
Brown AM. Excitation of afferent cardiac sympathetic
nerve fibres during myocardial ischemia. J Physiol
(Lond). 1967;190:35–53.
7.
Minisi AJ, Thames MD. Activation of cardiac
sympathetic afferents during coronary occlusion: evidence for
reflex activation of sympathetic nervous system during transmural
myocardial ischemia in the dog. Circulation. 1991;84:357–367.
8. Huang MH, Horackova M, Negoescu RM, Wolf S, Armour JA. Polysensory response characteristics of dorsal root ganglion neurones that may serve sensory functions during myocardial ischaemia. Cardiovasc Res. 1996;32:503–515.[Medline] [Order article via Infotrieve]
9.
Thames MD, Klopfenstein HS, Abboud FM, Allyn LM,
Walker JL. Preferential distribution of inhibitory cardiac
receptors with vagal afferents to the inferoposterior wall of the left
ventricle activated during coronary occlusion in the
dog. Circ Res. 1978;43:512–519.
10.
Armour JA, Huang MH, Pelleg A, Sylven C. Responsiveness
of in situ canine nodose ganglion afferent neurones to epicardial
mechanical or chemical stimuli. Cardiovasc Res. 1994;28:1218–1225.
11.
James TN. A cardiogenic hypertensive chemoreflex.
Anesth Analg. 1989;69:633–646.
12.
Baker DG, Coleridge HM, Coleridge JCG, Nerdrum T.
Search for a cardiac nociceptor: stimulation by bradykinin of
sympathetic afferent nerve endings in the heart of the cat.
J Physiol (Lond). 1980;306:519–536.
13. Euchner-Wamser I, Meller ST, Gebhart GF. A model of cardiac nociception in chronically instrumented rats: behavioral and electrophysiological effects of pericardial administration of algogenic substances. Pain. 1994;58:117–128.[Medline] [Order article via Infotrieve]
14. Malliani A, Schwartz PJ, Zanchetti A. A sympathetic reflex elicited by experimental coronary occlusion. Am J Physiol. 1969;217:703–709.
15. Sleight P. A cardiovascular depressor reflex from the epicardium of the left ventricle in the dog. J Physiol (Lond). 1964;173:321–343.
16. Meller ST, Gebhart GF. A critical review of the afferent pathways and the potential chemical mediators involved in cardiac pain. Neuroscience. 1992;48:501–524.[Medline] [Order article via Infotrieve]
17. Jacobus WE, Taylor GT IV, Hollis DP, Nunnally RL. Phosphorus nuclear magnetic resonance of perfused working rat hearts. Nature. 1977;265:756–758.[Medline] [Order article via Infotrieve]
18. Cobbe SM, Poole-Wilson PA. The time of onset and severity of acidosis in myocardial ischemia. J Mol Cell Cardiol. 1980;12:745–760.[Medline] [Order article via Infotrieve]
19. Hirsch HJ, Franz CHR, Bos L, Bissig R, Lang R, Schramm M. Myocardial extracellular K+ and H+ increase and noradrenaline release as possible cause of early arrhythmias following acute coronary artery occlusion in pigs. J Mol Cell Cardiol. 1980;12:579–593.[Medline] [Order article via Infotrieve]
20.
Cobbe SM, Poole-Wilson PA. Continuous coronary
sinus and arterial pH monitoring during pacing-induced
ischaemia in coronary artery disease. Br Heart
J. 1982;47:369–374.
21. Uchida Y, Murao S. Acid-induced excitation of afferent cardiac sympathetic nerve fibers. Am J Physiol. 1975;228:27–33.
22. Steen KH, Steen AE, Reeh PW. A dominant role of acid pH in inflammatory excitation and sensitization of nociceptors in rat skin, in vitro. J Neurosci. 1995;15:3982–3989.[Abstract]
23. Krishtal OA, Pidoplichko VI. A receptor for protons in the nerve cell membrane. Neuroscience. 1980;5:2325–2327.[Medline] [Order article via Infotrieve]
24.
Konnerth A, Lux HD, Morad M. Proton-induced
transformation of calcium channel in chick dorsal root ganglion cells.
J Physiol (Lond). 1987;386:603–633.
25.
Davies NW, Lux HD, Morad M. Site and mechanism of
activation of proton-induced sodium current in chick dorsal root
ganglion neurons. J Physiol (Lond). 1988;400:159–187.
26.
Bevan S, Yeats J. Protons activate a cation
conductance in a sub-population of rat dorsal root ganglion neurones.
J Physiol (Lond). 1991;433:145–161.
27. Krishtal OA, Pidoplichko VI. A receptor for protons in the membrane of sensory neurons may participate in nociception. Neuroscience. 1981;6:2599–2601.[Medline] [Order article via Infotrieve]
28. Waldmann R, Lazdunski M. H+-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels. Curr Opin Neurobiol. 1998;8:418–424.[Medline] [Order article via Infotrieve]
29. Nakatani T, Shinohara H, Fukuo Y, Morisawa S, Matsuda T. Pericardium of rodents: pores connect the pericardial and pleural cavities. Anat Rec. 1988;220:132–137.[Medline] [Order article via Infotrieve]
30. Eckert SP, Taddese A, McCleskey EW. Isolation and culture of rat sensory neurons having distinct sensory modalities. J Neurosci Methods. 1997;77:183–190.[Medline] [Order article via Infotrieve]
31. Hille B. Selective permeability: independence. In: Ion Channels of Excitable Membranes. Sunderland, Mass: Sinauer Associates; 1992:344–347.
32. Cook SP, Vulchanova L, Hargreaves KM, Elde R, McCleskey EW. Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature. 1997;387:505–508.[Medline] [Order article via Infotrieve]
33.
Maricq AV, Peterson AS, Brake AJ, Myers RM, Julius D.
Primary structure and functional expression of the
5HT3 receptor, a serotonin-gated ion
channel. Science. 1991;254:432–436.
34. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816–824.[Medline] [Order article via Infotrieve]
35. Sucher NJ, Cheng TPO, Lipton SA. Neural nicotinic acetylcholine responses in sensory neurons from postnatal rat. Brain Res. 1990;533:248–254.[Medline] [Order article via Infotrieve]
36.
Nicol GD, Cui M. Enhancement by
prostaglandin E2 of bradykinin
activation of embryonic rat sensory neurones. J Physiol
(Lond). 1994;480:485–492.
37. Allen TGJ, Burnstock G. The actions of adenosine 5'-triphosphate on guinea-pig intracardiac neurones in culture. Br J Pharmacol. 1990;100:269–276.[Medline] [Order article via Infotrieve]
38. Lewis C, Neidhart S, Holy C, North RA, Buell G, Suprenant A. Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature. 1995;377:432–435.[Medline] [Order article via Infotrieve]
39. Chen CC, Akopian AN, Sivilotti L, Colquhoun D, Burnstock G, Wood JN. A P2X purinoceptor expressed by a subset of sensory neurons. Nature. 1995;377:428–431.[Medline] [Order article via Infotrieve]
40. Kovalchuk YN, Krishtal OA, Nowycky MC. The proton-activated inward current of rat sensory neurons includes a calcium component. Neurosci Lett. 1990;115:237–242.[Medline] [Order article via Infotrieve]
41. Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M. A proton-gated cation channel involved in acid-sensing. Nature. 1997;386:173–177.[Medline] [Order article via Infotrieve]
42.
Tang CM, Presser F, Morad M. Amiloride selectively
blocks the low threshold (T) calcium channel. Science. 1988;240:213–215.
43.
Waldmann R, Bassilana F, de Weille J, Champigny G,
Heurteaux C, Lazdunski M. Molecular cloning of a non-inactivating
proton-gated Na+ channel specific for sensory
neurons. J Biol Chem. 1997;272:20975–20978.
44. Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger J, Rossier BC. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature. 1994;367:463–467.[Medline] [Order article via Infotrieve]
45. Alles A, Dom RM. Peripheral sensory nerve fibers that dichotomize to supply the brachium and the pericardium in the rat: a possible morphological explanation for referred cardiac pain? Brain Res. 1985;342:382–385.[Medline] [Order article via Infotrieve]
46. Bevan S, Winter J. Nerve growth factor (NGF) differentially regulates the chemosensitivity of adult rat cultured sensory neurons. J Neurosci. 1995;15:4918–4926.[Abstract]
47. Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 1998;21:531–543.[Medline] [Order article via Infotrieve]
48. Deanfield JE, Shea MJ, Selwyn AP. Clinical evaluation of transient myocardial ischemia during daily life. Am J Med. 1985;79(suppl 3A):18–24.
49. Malliani A. Significance of experimental models in assessing the link between myocardial ischemia and pain. Adv Cardiol. 1990;37:126–141.[Medline] [Order article via Infotrieve]
50.
Rosen SD, Paulesu E, Nihoyannopoulos P, Tousoulis D,
Prackowiak SJ, Frith CD, Jones T, Camici PG. Silent ischemia as
a central problem: regional brain activation compared in silent and
painful myocardial ischemia. Ann Intern Med. 1996;124:939–949.
51. Thamer V, Deussen A, Schipke JD, Tolle T, Heusch G. Pain and myocardial ischemia: the role of sympathetic activation. Basic Res Cardiol. 1990;85:253–266.
52. Francis GS, Goldsmith SR, Levine TB, Olivari MT, Cohn JN. The neurohormonal axis in congestive heart failure. Ann Intern Med. 1984;101:370–377.
53. Mitrani RD, Zipes DP. Clinical neurocardiology: arrhythmias. In: Armour JA, Ardell JL, ed. Neurocardiology. New York, NY: Oxford University Press; 1994:365–395.
54. Victor RG, Bertocci LA, Pryor SL, Nunnally RL. Sympathetic nerve discharge is coupled to muscle cell pH during exercise in humans. J Clin Invest. 1988;82:1301–1305.
55.
Rendig SV, Chalal PS, Longhurst JC.
Cardiovascular reflex responses to ischemia
during occlusion of celiac and/or superior mesenteric arteries.
Am J Physiol. 1997;272:H791–H796.
This article has been cited by other articles:
 |
|
 |
|
  T. Hattori, J. Chen, A. M. S. Harding, M. P. Price, Y. Lu, F. M. Abboud, and C. J. Benson ASIC2a and ASIC3 Heteromultimerize to Form pH-Sensitive Channels in Mouse Cardiac Dorsal Root Ganglia Neurons Circ. Res., July 31, 2009; 105(3): 279 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. McCord, H. Tsuchimochi, and M. P. Kaufman Acid-sensing ion channels contribute to the metaboreceptor component of the exercise pressor reflex Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H443 - H449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. O. Eshcol, A. M. S. Harding, T. Hattori, V. Costa, M. J. Welsh, and C. J. Benson Acid-sensing ion channel 3 (ASIC3) cell surface expression is modulated by PSD-95 within lipid rafts Am J Physiol Cell Physiol, September 1, 2008; 295(3): C732 - C739. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Henrich and K. J. Buckler Effects of Anoxia and Aglycemia on Cytosolic Calcium Regulation in Rat Sensory Neurons J Neurophysiol, July 1, 2008; 100(1): 456 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. A. Drummond, N. L. Jernigan, and S. C. Grifoni Sensing Tension: Epithelial Sodium Channel/Acid-Sensing Ion Channel Proteins in Cardiovascular Homeostasis Hypertension, May 1, 2008; 51(5): 1265 - 1271. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Paukert, X. Chen, G. Polleichtner, H. Schindelin, and S. Grunder Candidate Amino Acids Involved in H+ Gating of Acid-sensing Ion Channel 1a J. Biol. Chem., January 4, 2008; 283(1): 572 - 581. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Henrich and K. J. Buckler Effects of anoxia, aglycemia, and acidosis on cytosolic Mg2+, ATP, and pH in rat sensory neurons Am J Physiol Cell Physiol, January 1, 2008; 294(1): C280 - C294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sugiura, K. Bielefeldt, and G. F. Gebhart Mouse colon sensory neurons detect extracellular acidosis via TRPV1 Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1768 - C1774. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Poirot, T. Berta, I. Decosterd, and S. Kellenberger Distinct ASIC currents are expressed in rat putative nociceptors and are modulated by nerve injury J. Physiol., October 1, 2006; 576(1): 215 - 234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Bubien and D. J. Benos Molecular pH Probes: Mediators of Angina and Ischemic Preconditioning? Circ. Res., September 1, 2006; 99(5): 453 - 454. [Full Text] [PDF]
|
|
|
|
|
|
J. Yagi, H. N. Wenk, L. A. Naves, and E. W. McCleskey Sustained Currents Through ASIC3 Ion Channels at the Modest pH Changes That Occur During Myocardial Ischemia Circ. Res., September 1, 2006; 99(5): 501 - 509. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-P. Chu, N. Close, J. A. Saugstad, and Z.-G. Xiong ASIC1a-specific modulation of acid-sensing ion channels in mouse cortical neurons by redox reagents. J. Neurosci., May 17, 2006; 26(20): 5329 - 5339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Salinas, L. D. Rash, A. Baron, G. Lambeau, P. Escoubas, and M. Lazdunski The receptor site of the spider toxin PcTx1 on the proton-gated cation channel ASIC1a J. Physiol., January 15, 2006; 570(2): 339 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Chen, H. Kalbacher, and S. Grunder The Tarantula Toxin Psalmotoxin 1 Inhibits Acid-sensing Ion Channel (ASIC) 1a by Increasing Its Apparent H+ Affinity J. Gen. Physiol., June 27, 2005; 126(1): 71 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sugiura, K. Dang, K. Lamb, K. Bielefeldt, and G. F. Gebhart Acid-Sensing Properties in Rat Gastric Sensory Neurons from Normal and Ulcerated Stomach J. Neurosci., March 9, 2005; 25(10): 2617 - 2627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. M. Flake, D. B. Bonebreak, and M. S. Gold Estrogen and Inflammation Increase the Excitability of Rat Temporomandibular Joint Afferent Neurons J Neurophysiol, March 1, 2005; 93(3): 1585 - 1597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ditting, K. F. Hilgers, K. E. Scrogin, A. Stetter, P. Linz, and R. Veelken Mechanosensitive cardiac C-fiber response to changes in left ventricular filling, coronary perfusion pressure, hemorrhage, and volume expansion in rats Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H541 - H552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Price, R. J. Thompson, J. O. Eshcol, J. A. Wemmie, and C. J. Benson Stomatin Modulates Gating of Acid-sensing Ion Channels J. Biol. Chem., December 17, 2004; 279(51): 53886 - 53891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Hruska-Hageman, C. J. Benson, A. S. Leonard, M. P. Price, and M. J. Welsh PSD-95 and Lin-7b Interact with Acid-sensing Ion Channel-3 and Have Opposite Effects on H+-gated Current J. Biol. Chem., November 5, 2004; 279(45): 46962 - 46968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-P. Chu, J. A. Wemmie, W.-Z. Wang, X.-M. Zhu, J. A. Saugstad, M. P. Price, R. P. Simon, and Z.-G. Xiong Subunit-Dependent High-Affinity Zinc Inhibition of Acid-Sensing Ion Channels J. Neurosci., October 6, 2004; 24(40): 8678 - 8689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Deval, M. Salinas, A. Baron, E. Lingueglia, and M. Lazdunski ASIC2b-dependent Regulation of ASIC3, an Essential Acid-sensing Ion Channel Subunit in Sensory Neurons via the Partner Protein PICK-1 J. Biol. Chem., May 7, 2004; 279(19): 19531 - 19539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Wemmie, M. W. Coryell, C. C. Askwith, E. Lamani, A. S. Leonard, C. D. Sigmund, and M. J. Welsh Overexpression of acid-sensing ion channel 1a in transgenic mice increases acquired fear-related behavior PNAS, March 9, 2004; 101(10): 3621 - 3626. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ettaiche, N. Guy, P. Hofman, M. Lazdunski, and R. Waldmann Acid-Sensing Ion Channel 2 Is Important for Retinal Function and Protects against Light-Induced Retinal Degeneration J. Neurosci., February 4, 2004; 24(5): 1005 - 1012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Mamet, M. Lazdunski, and N. Voilley How Nerve Growth Factor Drives Physiological and Inflammatory Expressions of Acid-sensing Ion Channel 3 in Sensory Neurons J. Biol. Chem., December 5, 2003; 278(49): 48907 - 48913. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-P. Chu, X.-M. Zhu, W.-L. Wei, G.-H. Li, R. P Simon, J. F MacDonald, and Z.-G. Xiong Acidosis decreases low Ca2+ -induced neuronal excitation by inhibiting the activity of calcium-sensing cation channels in cultured mouse hippocampal neurons J. Physiol., July 15, 2003; 550(2): 385 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. N. Browning and D. Mendelowitz Musings on the Wanderer: What's New in Our Understanding of Vago-Vagal Reflexes?: II. Integration of afferent signaling from the viscera by the nodose ganglia Am J Physiol Gastrointest Liver Physiol, January 1, 2003; 284(1): G8 - G14. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Baron, E. Deval, M. Salinas, E. Lingueglia, N. Voilley, and M. Lazdunski Protein Kinase C Stimulates the Acid-sensing Ion Channel ASIC2a via the PDZ Domain-containing Protein PICK1 J. Biol. Chem., December 20, 2002; 277(52): 50463 - 50468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Babini, M. Paukert, H.-S. Geisler, and S. Grunder Alternative Splicing and Interaction with Di- and Polyvalent Cations Control the Dynamic Range of Acid-sensing Ion Channel 1 (ASIC1) J. Biol. Chem., October 25, 2002; 277(44): 41597 - 41603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J Allen and D. Attwell Modulation of ASIC channels in rat cerebellar purkinje neurons by ischaemia-related signals J. Physiol., September 1, 2002; 543(2): 521 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Lin, T. Ogura, and S. C. Kinnamon Acid-Activated Cation Currents in Rat Vallate Taste Receptor Cells J Neurophysiol, July 1, 2002; 88(1): 133 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kellenberger and L. Schild Epithelial Sodium Channel/Degenerin Family of Ion Channels: A Variety of Functions for a Shared Structure Physiol Rev, July 1, 2002; 82(3): 735 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xie, M. P. Price, A. L. Berger, and M. J. Welsh DRASIC Contributes to pH-Gated Currents in Large Dorsal Root Ganglion Sensory Neurons by Forming Heteromultimeric Channels J Neurophysiol, June 1, 2002; 87(6): 2835 - 2843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Anzai, E. Deval, L. Schaefer, V. Friend, M. Lazdunski, and E. Lingueglia The Multivalent PDZ Domain-containing Protein CIPP Is a Partner of Acid-sensing Ion Channel 3 in Sensory Neurons J. Biol. Chem., May 3, 2002; 277(19): 16655 - 16661. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-P. Chu, J. Miesch, M. Johnson, L. Root, X.-M. Zhu, D. Chen, R. P. Simon, and Z.-G. Xiong Proton-Gated Channels in PC12 Cells J Neurophysiol, May 1, 2002; 87(5): 2555 - 2561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Baron, R. Waldmann, and M. Lazdunski ASIC-like, proton-activated currents in rat hippocampal neurons J. Physiol., March 1, 2002; 539(2): 485 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Benson, J. Xie, J. A. Wemmie, M. P. Price, J. M. Henss, M. J. Welsh, and P. M. Snyder Heteromultimers of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons PNAS, February 19, 2002; 99(4): 2338 - 2343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Garcia-Anoveros, T. A. Samad, L. Zuvela-Jelaska, C. J. Woolf, and D. P. Corey Transport and Localization of the DEG/ENaC Ion Channel BNaC1{alpha} to Peripheral Mechanosensory Terminals of Dorsal Root Ganglia Neurons J. Neurosci., April 15, 2001; 21(8): 2678 - 2686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Sutherland, C. J. Benson, J. P. Adelman, and E. W. McCleskey Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons PNAS, December 14, 2000; (2000) 11404498. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. N. James Homage to James B. Herrick: A Contemporary Look at Myocardial Infarction and at Sickle-Cell Heart Disease : The 32nd Annual Herrick Lecture of the Council on Clinical Cardiology of the American Heart Association Circulation, April 18, 2000; 101(15): 1874 - 1887. [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Caterina, A. Leffler, A. B. Malmberg, W. J. Martin, J. Trafton, K. R. Petersen-Zeitz, M. Koltzenburg, A. I. Basbaum, and D. Julius Impaired Nociception and Pain Sensation in Mice Lacking the Capsaicin Receptor Science, April 14, 2000; 288(5464): 306 - 313. [Abstract] [Full Text]
|
|
|
|
|
|
P. Escoubas, J. R. De Weille, A. Lecoq, S. Diochot, R. Waldmann, G. Champigny, D. Moinier, A. Menez, and M. Lazdunski Isolation of a Tarantula Toxin Specific for a Class of Proton-gated Na+ Channels J. Biol. Chem., August 11, 2000; 275(33): 25116 - 25121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Baron, L. Schaefer, E. Lingueglia, G. Champigny, and M. Lazdunski Zn2+ and H+ Are Coactivators of Acid-sensing Ion Channels J. Biol. Chem., September 14, 2001; 276(38): 35361 - 35367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Sutherland, C. J. Benson, J. P. Adelman, and E. W. McCleskey From the Cover: Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons PNAS, January 16, 2001; 98(2): 711 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Askwith, C. J. Benson, M. J. Welsh, and P. M. Snyder DEG/ENaC ion channels involved in sensory transduction are modulated by cold temperature PNAS, May 22, 2001; 98(11): 6459 - 6463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Baron, R. Waldmann, and M. Lazdunski ASIC-like, proton-activated currents in rat hippocampal neurons J. Physiol., March 1, 2002; 539(2): 485 - 494. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||