Cdciun~,calcium channels, and calcium channel antagonists' DAVIDJ. T'MGGEE
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Sclzool of P l z a m c y , State University of New York, Buflako, NY 14260, U.S.A. Received September 25, 1989 f i r e e k ~ ,Do9. 1990. Calcium, calcium channels, and calcium channel antagonists. Can. J. Physiol. Pharmacol. 643: 1474- 1481. Voltage-dependent Ca2+ channels are an important pathway for Ca2+ influx in excitable cells. They also represent an important site of action for a therapeutic group of agents, the Ca2+ channel antagonists. These drugs enjoy considerable use in the cardiovascular area including angina, some arrhythmias, hypertension, and peripheral vascular disorders. The voltagedependent Ca2+ channels exist in a number of subclasses characterized by electrophysiologic, permeation, and pharmacologie criteria. The Ca2+ channel antagonists, including verapamil, nifedipine, and diltiazem, serve to characterize the 6, channel class. This channel class has been chmcterked as a phamcologic receptor, since it possesses specific drug-binding sites for both antagonists and activators and it is regulated by homologous and heterologous influences. The Ca2+ channels of both voltage- and ligand-regulated classes are likely to continue to be m j o r research targets for new dmg design and action. Key words: calcium, calcium channels, calcium antagonists, 1,4-dihydropyridines, channel regulation, receptor regulation. Tlueem, D. J. 1990. Calcium, calcium channels, and calcium channel antagonists. Can. 9. Physiol. Bhamacol. 68 : 1474- 1481. Les canaux Caw ++endants de la tension sont une voie importante pour l'influx de Ca2+dans les cellules excitables. Ils reprksentent aussi un site d9action important pour un groupe d'agents thCraputiques, les antagonistes des canaux Ca2+.Ces drogues sont utilishs abondament dans le domaine cardiovasculaire pour traiter 19angine,certaines arythmies, l'hyprtension et les affections vasculaires pCriphCriques. Le groupe de canaux Ca2+ &pendants de la tension se ramifie en des sous-classes caractCrisCes par des critkres pharmacologiques, de permcation et Clectrophysiologiques. Les antagonistes des camux Ca2", incluant le vQapamil, la nifdipine et le diltiazem, permettent de caractkriser la classe de canaux L. Les canaux de cette classe ont CtC considCrCs tels des rdcepteurs phamacologiques du fait qu'ils posskdent des sites de fixation spCcifipes tant pour les activateurs que pour les antagonistes et parce qu'ils wnt rCgulCs par des sources hCtCrologues et homologues. k s canaux Ca2+ des classes rCgulCes par des ligands et par la tension continueront d'8tre des sujets de recherche importants pour la conception et l'actisn des drogues. Mots clds : calcium, canaux calcium, antagonistes da calcium, dihydro-l,4-pyridines, rkgulation des canaux, rkgulation des rbcepteurs. [Traduit par la revue]
Introduction Calcium is a charismatic cation, coupling membrane excitation to cellular response (Campbell 1983). In excess, calcium serves also as a culprit cation mediating cell damage and cell death during cellular calcium overload (Cheung et d.1986). To fulfill its role in stimulus -response coupling phenomena, calcium must be a closely regulated species. The regulation of calcium depends on the following set s f considerations: (i) the resting intracellular concentration of free ionized Ca2+ is -5 x 1W8 M or less; (ki) during cell excitation, the concenM; tration of intracelllular ionized Ca2+ rises to -5 x (iii) the function of elevated intraceuular CaB is to transmit information from membrane events; and (kv) information transmission is accomplished through interaction of Ca2+ with a group of homologous Ca2+-modulated proteins or receptors. Accordingly, the cell coordinates a set of processes that regulate the transport and sequestration of Ca2+ and which maintain the low intracellular resting free levels of Ca2+ in the face of high inwardly directed concentration and electrochemical gradients. These processes are depicted schematicdly in Fig, 1. In principle, each of the Ca2+ control processes depicted in Pig. 1 represents a potential site for the interaction of specific drugs. Accordingly, the following drug classes may be envi'This paper was presented at the CFBS Symposium on Calcium Channels, held in Calgary, Alta., Canada, June 16, 1989, and has undergone the Journal's usual peer review. Printed in Canada !I m p r i d au Canada
sioned (Jawis et d.198'7): (i) agents modulating sarcolemmal Naf -Ca2+ transport; (ii) agents modulating sarcolemmal Ca2+ ATPase; (iii) agents modulating voltage-gated Ca2+ channels; (iv) agents modulating ligand-gated Ca2+ channels; (v) agents modulating Hnitochondrid Ca2+ uptake and release; (vi) agents modulating sarcoplasmic and endoplasmic reticulum CaD uptake m d release. In practice, although agents are known h t interact at all of these sites, the only class of drugs to have achieved therapeutic significance is that interacting at the plasmalemmal voltage-gated Ca2+ channels. However, the considerable developments taking place in the elucidation of the structure and function of the Ca2+ release channel of sarcoplasmic reticulum through specific ligands of the ryanodine class (Smith et al. 1988) suggests the possibility of drug development for this site including cardiac inotropic agents.
Ca" channels a d G2 channel antagonists The Ca2+ chmnel antagonists, including the clinically available verapamil, nifedipine, and diltiazem, are a chemicdly heterogeneous group of agents (Fig. 2) that enjoy major use in a variety of cardiovascular disorders (Table 1). Although their primary general uses are in the relief of angina in its severd forms and in the control of hypertension, the Ca2+ channel antagonists enjoy a spectrum of actions that are considerably more diverse (Fleckenstein 1983; Table 2). Voltage-gated Ca2+ channels are widespread in excitable cells (Bean 1989). Hence, the relative selectivity sf action of the available antagonists has excited comment. In part, the selectivity of action sf the agents depicted in Fig. 2 arises from +
TABLE1. Therapeutic uses of calcium channel antagonists Antagonist Veraparnil (1)
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Use
FIG. 1. Schematic representation s f cellular Ca2+ regulation. Depicted are several processes of membrane and intracellular regulation including the following: 1, Na+-Ca2+ exchange; 2, receptoroperated CaZ+ channels; 3, potential-dependent Ca2+ channels; 4, Ca2+ leak pathways; 5, ATB-dependent Ca2+ uptake into the sarcoplasmic reticulum; 6 , Ca2+ release from the sarcoplasmic reticulum through the Ca2+ release channel; 7, ATP- and calmodulindependent Ca2+ transport across the plasma membrane; 8, CaZ+ uptake into mitochondria; 9, Na+ -Ca2+ exchange in mitochondria. These processes are not necessarily of equal importance in all cell types or under all conditions of cell stimulation.
Nifedipine (no
Diltiazem (I111
Angina Exertional Brimmetal's Variant Arrhythmias Baroxy s m l supraventricular tachyarrhythmias Atrial fibrillation and flutter Hypertension Hypertrophic cardiomyopathy Raynaud's phenomenon Cerebral vasospasm (post hemorrhage) NOTE:Classes I , II,tad III are as defined by the Wodd Health Organization. Number of plus signs indicates extent of use: being very common; -, not used. a , nimo-
+ + +,
dipine.
Ester functions optimum antagonism: -COeR>COMe>CM > H
)=
Chiral center : stereoselectivity
-Aryi ring torsion angle Verapamil
Substituents o 2 rn >> p Electron withdrawing> Electron releasing
Nifedipine
Small alkyl groups optimum
Bulk tolerance selectivity
FIG.3 . The structural requirements for 1,4-dihydropyridine interaction with Ca2+ channels. FIG.2. The structural formulae of Ca2+ channel antagonists.
their selective interactions at only one channel type. At least three major classes of voltage-gated Ca2+ channels exist and these can be differentiated by a variety of criteria including permeation selectivity, electrophysiologic characteristics, and pharmacologic sensitivity w a n 1989; Fox et al. 1989; Table 3). It is the L channel class, characterized by activation at depolarized membrane potentials and large conductance, that dominates many cardiovascular functions and which is sensitive to the 1,4-dikydropyridine (nifedipine) and other classes of antagonists. This class of channel likely sustains functions that demand large and relatively sustained influxes of Ca2+. In contrast, T channels are activated at more polarized membrane potentials, are of low conductance, and inactivate rapidly, suggesting a role in pacemaking and related trigger functions. N channels appear to be confined to neurons
where they mediate, together with E channels, neurstransmitter release (Miller 1987).
6a2 channels as phamcologic receptors From the pharmacologic perspective, a particularly important distinction between the several classes of Ca2+ channels is provided by drugs that act selectively at one or the other channel type. Although the best characterized of these agents are those effective at the L channel, the availability of the peptide o-conotoxins (Gray et al. 1988) and spider toxins of less well-defined structures (Bindokas and Adams 1989) makes their characterization possible. However, potent and selective ligands for the T channel class await definition. It is likely that voltage-gated ion channels belong to a channel family that exhibits substantial structural homology (Catterdl 1989; Jan and Jan 1989). Accordingly, it may be expected that drugs interacting at one class of Ca2+ channel may also interact at other classes (Triggle et al. 1989). Consistent with this, some +
CAN. J. PHYSIOL. PHARMACOL. VOL. 68, 19%
TABLE 2. Additional and potential uses of calcium charnel antagonists
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Cardiovascular Atherosclerosis Cardioplegia Cerebral ischemia, focal Cerebral ischemia, global Congestive heart failure Hypertrophic cardiomyopathy Migraine Mywardid infarction Peripheral vascular diseases Pulmonary hypertension Subarachnoid hemorrhage
Nonvascular smooth muscle Achalasia Asthma Dysmenorrhea Eclampsia Esophageal spasm Intestinal hypermotility Obstructive lung disease Premature labor Urinary incontinence
Other AIdosteronisrn Cancer chemotherapy Epilepsy Glaucoma Manic syndrome Motion sickness Spinal cord injury Tinnitus Tourette9sdisorder Vertigo
TABLE3. Properties of plasrndemal calcium channels Channel class
Activation range (mV) Inactivation range (mV) Inactivation rate Conductance @S) Permeation 1,4-DHB sensitivity a-Conotoxim sensitivity
- 10 -60 to -10 Very slow 25 Ba2+ > Ca2+ Sensitive Sensitive? (neurons) Insensitive (muscle)
-70 - 1 0 0 to -60
Rapid 8 ~
~
=2 ca2+ +
Insensitive Insensitive
- 30
-120 to -30 Moderate 13 Ba2' > Ca2+ Insensitive Sensitive
NOTE:Data were computed from a variety of sources and are not intended to suggest h a t these properties are sirapIarly characteristic of each c h m d class. 1,4-DHP, 1,4-dihydropyridine.
(+) S 202-794
- R 202-791
COOMe
(-1 S Boy k 8644
(f )R Bay k 8644
FIG. 4. Enantiomeric pairs of 1,4-dhydropyridines with activator -
(S)or antagonist (18) priperties. 1,4-d&ydropyridiHnes have been reported to interact at T channnels (Coben et dal. 1988). The pharmacdogic sensitivity of Ca2+ channels suggests that they (and other ion channel types) should be regarded as ghwmacologic receptors. This cliassificatiora may be useful, since it suggests that as pharmac~lsgicreceptors ion channels
FIG. 5. Arrangement sf drug binding sites on the Ca" channel depicting the sites linked allostericdly one to the other and to the p r meation and gating machinery s f the channel.
should have certain general properties. These are as follows: (i) presence of discrete drug binding sites with defined stmcture -activity relationships; (ii) existence of activator and antagonist ligands; (E'ii) ccsrrelatitioras between biding and
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HOE 466
MCN 6186
MDL 12,330A FIG. 6 . Structural formulae of agents that interact at the @a2+channel at sites distinct from those occupied by the classical antagonists s f Fig. 2.
6 7 8 9 1 0 -Bog 1658,Binding (Gut)
5 6 7 8 9 1 -log IC5(3,Binding (Heart)
0
6 7 8 9 1 8 -log IC50, Binding (Brain)
Fro. 7. Correlation of binding and phannacologic affinities for a series of B ,4-dihydropyridines. In each panel the binding and phamacologic activities of a series sf 8,4-dihydropyridines are compared to determine whether a correlation exists and whether this is I: 1. (a) Guinea pig ileal longitudinal smooth muscle: binding, displacement of [3H]nitrendipine, phamcology, and inhibition of K+ depolarization-induced response (tonic component). Data from Bolger et al. (1983). (b) Cardiac tissue: binding in rat heart, displacement of [3H]nitrendipine, p h m c o l o ~ and , inhibition of paced cat papillary muscle. Data from Janis et al. (1987) and Rdenkirchen et al. (8979). (c) Brain tissue: binding, displacement of [3H]nhodipine in rat brain, pharmacology, and inhibition of K' depolarization-induced tension responses in rabbit aorta. Data from Bellemann et al. (1983). Dashed lines represent 1: 8 equivalency and solid lines represent the regression.
pharmacologic activities of drugs; (iv) the regulation of channel number and function by heterologous and komologous influences including disease states. The L category of Ca2* channel satisfies all of these expectations. Three discrete categories of drug binding site have been characterized on the al-subunit of the Ca2+ channel. Defined structure -activity relationships exist, including stereoselectivity, for each of these sites and have been best characterized for the 1,4-dihydropyridines (Janis et al. 1987; Triggle et al. 1989; Fig. 3). Of particular interest the 1,4-dihydropyridine site acconamodates both activator and antagonist ligands that interact with a remarkable enantiomeric specificity (Hof et al. 1986; Franckowiak et al. 1985; Triggle et al. 1989; Fig. 4). The existence of activator and antagonist 1,4-dihydropyridines suggests the possible role ~f endogenous ligands for the channel whose properties are mimicked by these synthetic agents. The existence of endogenous ligands remains to be established
unambiguously, but several candidate molecules have k e n considered (Triggle 1988). Each of these classes of binding sites is linked to the functional machinery of the Ca2* channel and one to the other by a set of allosteric interactions (Fig. 5). It is perhaps unlikely that ody three primary classes of binding sites exist and several recent observations suggest that other structural classes of drugs, including the diphenylbutylpipridines (pimozide, fluspiriline), benzolactams (HOE 16Q),lactamides (MDL 12,3308), and ethynylbenzenealkanmines (McN 6186), may also interact at distinct sites on this channel (Rampe and Triggle 1989) (Fig. 6). The structure-activity relationships for the Ca2+ channel drugs originally defined from pharmacologic data have been complemented by radioligand binding studies, particularly for 1,4-dihydropyridines (reviewed in Triggle and Janis 1984; Janis et al. 1987). Nigh afinity binding sites for nitrendipine,
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TABLE4. Regulation of calcium channels Radiofigand Treatmemtlcondition
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(A) Homologous regulation Chronic drug action Oral nitrendipine, v e r a p a d , diltiaern (28 days) i. v . nifedipine 420 days) Nifdipine % Bay K 864-4 Chronic activation K9 depolarization (4 days) (B) Heterologous regulation Phenylephrine (6 days) Morphine (C) Other chronic regulation Ethanol k d
Species
Mouse
Nitrendipine Brain
Rat
Nitrendipine Heart Brain PN 200 110
PC12 PC 12
nc nc nc
1 49% 1 23% 1 29% nifedipine 1 24% Bay K 8644
1 62% B-rec 1 65% 0-rec
kit
Rat
Nitrendipinel utems
Rat ((SMR) (24 weeks) Rat (SHR) (4 - 15 weeks)
Nitrendipinel hart Nitrendipinel brain
Ischemia (60min hypoxia)
Rat
Ischemia bilateral ligation
Gerbil
Muscular dysgenesis
Mmse
Nitrendipinel heart Nitrendipinel brain (frontal cortex) Nitrendipinel skeletal muscle
H u m
PN 200 110
Q
Ca2+influx decreased
d
nc
1 32%
1 39% a-rec
e
nc
1 60%
nc nc
Thymid
Source
1 50%
Nimodipinehrain Nitrendipinel brain Nitrendipinel heart PN 200 1101 muscle Nitrendipinel heart
Rrpt Rat
Human
Clinical Cardiomyopathy
45Ca2f influx decreased
Nitrendipinel heart Nitrendipinel brain
Insulin (21 days)
Hypertension
1 40% (not diltiazem)
kit Mouse
Other
nc
Witrendipine
Rat (SMRISP)
(D) Disease states Experimental Hypertension
~ I I ~ X
PC12
NaCl
Hyperthyroid (5 days) Hypothyroid (PTU) Estrogen (4 days)
Tissue
f
nc
nc
1 42%
nc nc nc
1 26% t 96%
t 55%
t 43%
nc
1 36% 6-rec B 23 % P-rec 45Ca29influx increased
k
nc 0-rec, nc Na9 channel
r
I
t 2 B -40 % (striaturn, thalamus hipgocampus)
nc
1 14%
1 48%
1 26%
Absent nc
t 25%
NOTE:nc, no change; 0-rec, 8-adreraoceptors; bp, blood pressure; a, Pama et al. (1985); b, Gengo et d.(1988a); c, Skattebol et d. (1989): d, Dehrme et al. (1988); e, Gengs et d. (1988b);j,~ u a r m a ramd El-F-ragr (1984); g, Ddin et al. (1987); h. %us et al. (1984); i, Garthoff and Bellemam (1987); j , Desnuelle et al. (1986); k , Hawthorn et d. (1988); 1, Batha (1987); m, Chatelaim et d. (1984); m, Ishii et dal. (1986); o, Nayler et d.(1985); p, Kenray et d. (1986); q, Pincon-Raymond et d. (1985); r, Wagner et d. (1989).
PN 200 110, and other 1,4-dihydropyridines are found in mernbrame fractions from excitable tissues including smooth a d cardiac muscle a d neuronal preparations. The extent to which these binding affinities correlate with the corresponding g h a m a ~ % o g iaffinities c is tissue and stimulus dependent. In K+-depolmizd smooth muscle, there is generally a 1: 1 rela-
tionship between binding and p h ~ a c o l o g i cactivities; in cardiac muscle, the same rank order of activities is observed, but the correlation reflects low pharrnacologic affinities, and in meuronal preparations similar or identical binding affinities are observed but in the frequent absence of observed gharmcslogic activities (reviewed in Triggle and Sanis 1984; Janis
TABLE5. Voltage-dependent interactions of 2,4-dihydropyridines in cardiac cells (Wei et al. 1989) Polarized
KD
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(x
Depolarized
Bm, KD *max M) (fmollmg) ( x 10-9 M) (fmollmg)
FIG. $. Representation of ion channel cycling between resting, open, and inactivated states. Dmgs may bind (*) preferentially to one or more of these states.
et A. 198'3; Triggle et d. 1989; Fig. 7). These correlations accord with the observed pharmacologie and therapeutic profile of the I ,4-dihydropyridine Ca2+ channel antagonists and are consistent with the 1,4-dihydropyridine site (and sites for the other drug classes) being associated with the voltage-gated Ca2 channel. A characteristic property of pharmcologic receptors is their regulation by homologous and heterologous factors including disease states (Ferrmte and Triggle 1990). CaD channels, in common with pharmacologic receptors, are plasmdemmal proteins and are biosyaathesized and exported by very similar processes. It is anticipated that Ca2+ channels should, therefore, be subject to similar regulatory influences. This has been realized. Chronic channel activation, chronic drug exposure, hormone influence, and specific disease states are d l associated with altered or aberrant expression of Ca" channel numbers and function (Table 4). It is clear therefore that Ca" channels do fulfill the several criteria that define pharmacologic receptors. Accordingly, this view of ion channels may be useful for defining faarther avenues of experimentation. Further support to this receptorchannel concept is provided by observations that voltagedependent Ca2+ channels, in c o m o n with pharrnacologic receptors, may also be directly linked to one or other classes of G proteins and that G protein ligands may therefore modaslate channel function and properties (Brown and Birnbaumer 1988). +
The selectivity of action of Ca2 channel antagonists Despite the widespread availability of Ca2+ channels in excitable tissues, the therapeutically available Ca2 channel antagonists exhibit a very considerable selectivity of action. Such selectivity m y 9 in principle, have a variety of origins including the following: (i) pharmacokinetic factors - tissue distribution, absorption, and elimination; (ii) Ca2+ channel class - stimuli mobilizing Ca2+ from intracellular sources or +
+
KI
, Cel Is
Depolarized
FIG.9. Correlation between binding affinities for a series of activator ( S ) and antagonist (R) 1,4-dihydrspyridisaes to polarized (5 mM KCI) and depolarized (50 mM KCl) neonatal rat ventricular myscytes. The dashed lines represent 1H: l equivallency and the solid lines represent the regression. Data from Wei et al. (1989).
from non-L type Caw channels will not be sensitive to the existing antagonists; (iki) state-dependent interactions apparent drug affinity depends on channel state; (iv) pathological state of tissue - expression or function sf channels may be altered in disease states. The state-dependent interactions sf Ca2+ channel drugs are now very clearly realized to be one of the important determinants of the pharmacologieiDy and clinically observed tissue selectivity. According to the ' boddated receptor" hypothesis, the observed affinity sf a charnel active drug depends on its affinity for or access pathway to the resting, open, or inactivated states of the channel (Hondeghem and Katzung 1984; Fig. 8). Electrophysiologic investigations indicate very clearly that the 1,4-dihydropyridine antagonists interact preferentially with deplarized states sf the channel (Sanguiaaetti amd Kass 1984; Triggle 1989). Thus, the consistently observed high affinity interactions seen with 1,4-dihydropyridimes in membrane preparations arises from their interactisns with an inactivated state sf the channel favored by the depolarized state. Accordingly, the tissue- and stimulus-determined equilibrium of Fig. 8 will determine the apparent affinity for nifedipine and other 1,4-dihydmgyridine antagonists. Conditions of persistent depolarization (K+ depolarization or smooth muscle tone) will enhance drug affin-
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CAN. B. PHYSIOL. PHARMACOL.
ity. It is likely that such considerations underlie both the smooth and cardiac muscle selectivity of the I$-dihydropyridines and the observed regional vascular selectivity of these agents (Nelson and Worley 198%). The voltage-dependent interactions of the 1,4-dihydropyridines can also be observed t h o u g h radiofigand binding studies in intact cells under polarized and depolarized conditions ( K o h b u n et ale 1986; Wei et d o1989). In neonatal rat ventricular rnyocytes, [%](PN 200 110) binds with higher affinity to the depolarized state, an affinity change determined exclusively by a reduetion in the dissociation rate constant in the deplarized state (Table 5). This depslarization-dependent increase in affinity is shared by other 1,4-dihydropyridine antagonists (Fig. 9). Of particular interest, however, the interactions of 1.4-dihydrspyridine activators are essentially independent of membrane potential ((Pig. 9; Table 5). This voltage independence underlies previous observations that the pharmacologic properties of 1,4-dihydropyridiwe activators switch from activator to antagonist according to membrane potential (Kass 1987). The B,4-dihydrspyridines are thus mo%ecularchameleons changing their properties, both quantitatively and qualitatively, according to membrane potential.
Conclusions The therapeutic and molecular exploitation of the Ca2+ channel constitutes a remarkably fast-developing area that owes much to a small group of drugs, the Ca2+ channel antagonists. These agents have defined a new therapeutic modality (Fleckenstein 1983) and have served as molecular tools with which to dissect the channel. Continued analysis of the several classes of Ca2+ channel seems likely to be rewarding to clinicians and basic scientists alike.
Preparation of this work was supported by grants from the Natisnd Institutes of Health (HL 16003). Additional support from the Miles Institute for Breclinical Pharmacology is grateM l y acknowledged. BATRA, S. 1987. Increase by estrogen of calcium entry and calcium channel density in uterine smooth muscle. Br. J. Phamacol. 92: 389-392. BEAN,B. P. 1989. Classes of calcium channels in vertebrate cells. Annu. Rev. Physiol. 51: 367-384. BELLEMANN, 'P., SCHADE, A., and TOWART, R. 1983. Dihydropyridine receptor in rat brain labeled with [3H]nimdipine. Proc. Natl. Acad. Sci. U.S.A. 88: 2356-2360. BINDOKAS, V. P., and ADAMS, M.E. 1989. w-AGA-I: a presymptic calcium channel antagonist from venom of the funnel web spider, Agelenopsis uperta. B. Neurobiol. 20: 17 1 - 188. BOLGER,G. T., GENGO,p, K ~ C K O W S KR., I , LUCHOWSKI, E., SIEGEL,H.,JANIS,R. A., TRIGGLE,A. M., and QIGGLE, D. J. 1983. Characterization of binding of the Ca2+channel antagonist, [3H]mitrendipine, to guinea pig ileal smooth muscle. J. Pharmcol. Exp. Ther. 225: 291-310. BROWN, A. M., and BIRNBAUMER, k. 1988. Direct G protein gating of ion channels. Am. 3. Physiol. 254: H481 -H410. CAMPBELL, A. K. 1983. htracellular calcium. Its universal role as regulator. Wiley & Sons, Chichester and New York. CATTERALL, W. A. 1989. Structure and function of voltage-sensitive ion channels. Science Washington, BC) , 242: 50 -6 1. CHATELAHN, P., DEMBL,D.,and RQBA,J. 1984. Comparison of [3H]nitrendipinebinding to heart membranes of nomotensive and spontaneously hypertensive rats. J. Cardiovasc. Phamacol . 6: 228 -223.
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