INDEX

Acetylcholine, 202 Alternative splicing (continued) Acetylcholine receptors, nicotinic , 108 in Cav2genes, 385, 387-396 Action potentials (APs), 248, 254 therapeutic considerations, 396 Adaptor proteins , 241-242 in Cav3genes, 396-397 Adrenal fasciculata cells, 2I5-2I6 considerations for drug development, 400 Adrenal glomerulosa cells, 2 I5 identifying and confirming splice isoforms of a-Adrenergic modulation, 201 Caygenes, 374, 376 z I3-Adrenergic receptors (I3-AR), 348 in L-type Ca + genes, 379-385 I3-Adrenergic stimulation, 199 confers oxygen sensing to Cavl.2 Adrenocorticotropic hormone (ACI1I), 200, channels , 382 215-216 modifies inactivation, 380 eo-Agatoxins. 105 modifies pharmacology of Cavl.2, w-Aga-IA , 105-106 380-381 w-Aga-I1A and o>-Aga-I1B, 106 nomenclature of splice variants, 377, 379 processing of pre-mRNA, 375- 377 w-Aga-IIIA, o>-Aga-I1ill, and o>-Aga-IIID, 106 splice isoforms of Ca and Ca subunits , o>-Aga-IVA, 100,110,I II, 128,389 vl3z v134 398-400 and depolarizing shifts in activation voltage, I I I-I 14 AM-336 : see o>-CTx-CVID inhibits inward current by altering Amiloride, 194 chann el gating, I I 1-112 AMPA receptors, 320-321 knockoff of, 113 Amygdala neurons, central, 288 Analgesia, 163-165; see Pain sensitivities of splice forms of Cav2.1 to, Anandamide, 194 387 Anesthetics, 193 splice-form specific affinity for Cav2.1, Angiotensin II (All ), 202 126-127 structure, 157, 159 ANP: see Atrial natriuretic peptide Antiepileptics, 191, 193,213 w-Aga-IV A binding site, 124-126 Antihypertensive agents, 190, 384 low-affinity, 124-126 Antipsychotics, 193-194 o>-Aga-IVB (ro-Agatoxin-TK) , 159 Anxiety , increased Agelena opulenta, 146 in Cav2.3 knockout mice, 289 Agelenopsis aperta , 105, 106, 145, 146, 189 AP repolarization (afterhyperpolarization), Aldosterone, 215 254-255 Alternative splicing, 370 Arachidon ic acid (AA), 204 in Caval genes, 371-372 Assassin bug (Peirates turpis), 148, 159 C-terminal domain, 373 Ataxia, 283-284, 306, 307, 311-314,317,319 extracellular domain IV 53-54 linker, 372 in Cav2.1 knockout mice, 282-283 how many splice variants can be co-Atracotcxins. 106 generated from a Caval gene, w-Atracotox in-Hv2a, 106, 158 373-374 Atrax sp. lllawarra, 106 intracellular domain 11-111 loop (L . ), II III Atrial natriur etic peptide (ANP/AN F), 203, 215 372-373

411 412 INDEX

Atrial tachycardia-inducedelectrical remodeling, Calmodulin (CaM) (continued) 209-210 interactions with al C, 257 Auditory hair cells, 279-280 determinants of COl and CDF in alC, 257-258 Baclofen, 202 Calmodulin (CaM)-aICinteractions, 257-258 BAPTA,249 constitutive, 258-259 Barbiturates, 193 lobe-specific, 259-260 Benzothiazepinefunction, individual residues Calmodulin (CaM) tethering, non-contiguous critical for, 42 sequencesinvolvedin,259 Benzothiazepines, 28 Calmodulin kinase II (CaMKII), 247 Bicucullinemethobromide (BMB), 294 associates with L-type channel, 261 BK channels, 251-256 as frequency detector for CDF, 260-262 Black (Dendroaspis polylepispolylepis), autophosphorylation,260 116, 148 Calmodulin kinase II (CaMKII)-aICinteractions Bradykinin,203 . CDF depends upon, 261-262 Brazilianarmed spider (Phoneutria nigriventer), Calmodulin kinase II (CaMKII) substrate, alC 145, 146 subunit as, 261 Calmodulin kinase N (CaMKN), 246-248 CacnaJa gene (see Ca,2.I channels), 282, 283, Calmodulin kinase kinase (CaMKK), 245-248 306,307,309,311,312 Carbachol,201 Cacnalb gene (see Ca,2.2 channels), 284-287 Cardiac functions, 295 Cacna2d,318 Ca,I.2 channel and, 278, 384 CacnaJe gene (see Ca,2.3channels), 287-293 Cardiac hypertrophy, 207-209 CacnaIfgene (seeCa,I.4 channels), 308, 312 Cardiac muscle, 39, 195 2 Cacnb4,318-319 Ca + currents in Cacng2 ,319-321 distributionofT-type, 195, 197 CacnlaJ gene (see Ca,l.l channels), 304, 305 Cardiac myocytes, 278-279 Caenorhabditis elegans, mutations in, 322 Cardiac pacemaker activity, Ca,I.3 channel and, 280 CAG expansions, 306, 311 Cardiac pacemaking and abnormal electrical Calcicludine, 148 activity,210-212 binding site, 128 Cardiomyopathy, 207-209 effects on gating and permeation, 117 Cardiovasculardisease, treatment of, 79-80 Calcineurin, 247 CASK,241 -242 , dihydropyridine-like inhibitionby, Cav/34 gene structure, 398-400 116 Ca.I (L-type)channel inhibitors, 29 Calcium channel antagonists, L-type aliphatic, 30 actions, 25-27 nonselective, 30 cardiovascular profile, 23 weak,30 conbrcrlndications, 53-54 Ca.l (L-type)channel subtypes, pharmacologyof, differentialinteraction with L-type calcium 38-39 channel splice forms, 39 Cayl (L-type) channels, 27-28, 103-104, drug structures, 24 277-281;see also L-type channels interactionswith non-ion channel targets, 44 L-type activator and antagoniststructures, 35 interactionswith non-L-type channels, 46 L-type agonists, 32 perspectiveand future directions, 54-56 pharmacology pharmacokineticclassification,50 classes of drugs, 28-31 sites of action, 43-47 clinical action due to interaction at non­ that block non-L-type channels, 46 channel receptors,47 therapeuticuses, 23 localizationand definition receptor sites, vascularselectivity, 27 40-43 Calciumchannel blockers, classical, 190 peptide , 32-33 Calciumchannels; see also specijictopics sites of drug action, 43-47 nomenclatureof voltage-operated, 187 structure-activity relationships, 33-38 Calcium-dependentfacilitation (CDF), 256-262 activation and inactivation relationshipsfor Calcium-dependentinactivation (COl), 256-261, Ca2+ currents, 184 381 Ca.I .I , 304-306; see also Calcium channel Calcium regulation,cellular, 22 antagonists Calmodulin (CaM) hypokalemicperiodic paralysis and mutations calcium channels and, 257-262 in, 304-306 calcium-dependentgating, 256-257 INDEX 413

Cav\.2,278-279 Cav2,3 knockout mice, R-type currents in,288-289 cardiacand smooth muscle spliceforms,39 Cav2.3 modulators, 83; see SNX-482 spliceisoforms, 379-382,384 Cav3 (T-type) channels, 104, 183,216--217, therapeutic considerations, 384 293-294 voltage dependent gatingkinetics, 12-13 in cardiovascular physiology and pathology, Cay 1.2channels; see alsoCalmodulin 210-212 N-terminal variants of, 384 chemical structuresof drugs blocking, 192, truncated formsof, 382 193 Cavl .2 gene,structureof human, 378 in endocrine system,214-216 Cav 1.3 in growthanddevelopment, 205-210 spliceisoforms of, 384 growthand differentiation, 205-207 sitesof splicing, 384-385 tissueremodeling and repair,207 therapeutic considerations, 385 in humancells, 195-196,200 uniquepharmacology, 38-39, 104 modulation, 199-204 Cav 1.3channels, 279-281 molecular pharmacology of Ca.J channels,

Cavl .3 knockout miceare deaf,279-280 183,188-194 Cav\.3 gene, structure of human,383 inorganic ions, 189 Cav2 channel antagonists, 7J-80 in nervoussystemphysiology and pathology, Cav2 channels, 73-74, 281-293 212-214 2 Cav2 .1channelmodulators, 80-83 T-typeCa + currentsand associated channel Cav2.! channelopathies, 81-83 proteins Cav2.! channels (P- or P/Q-type channels), electrophysiological characterization, 160-163,282-284,399,400 184-186 mutations, 306--318 molecular characterization, 186--187 P/Qcurrentdensityand ataxicphenotype, tissuelocalization, 194-199 283-284 in vivo pharmacology and function, 204 P/Q-type channelis encoded solelyby, 283 Cav3.! channel, 293-294 and pain,80 Cav3 .1 knockout mice,burstmodefiringof action restingstateanduse-dependent blockof, 2, 3 potentials lackingin neuronsfrom, spliceisoforms of, 385, 387-391 293-294 Cvterminus, 390-391 Cellgrowth, proliferation, and differentiation, intracellular domainII-III loop(LU_III), 205-207 390 Cellularfunctions of calciumchannel subtypes, intracellular I-IIloop(LI-U), 387-388 237-238 ;see alsospecificcellular IVS3-IVS4 extracellular linker,389-390 functions selectivity, 100-102, 126--128 Central amygdala (CeA)neurons,288 Cav2.1 gene,structureof, 386 Cerebellum, 282, 315, 317 Cav2.2 (N-type) channelantagonists, 165 Channel block, accounting for molecular Cav2.2 (N-type) channels, 101-103,284-287,351 mechanism of, 5, 7

oi- affinityfor partiallyinactivated UIA channels: see Cav2.1 channels

vs. noninactivated, 121 UIB channels: see Cav2.2 channels potencyand selectivity of co- for, UIC channels: see Cay 1.2channels 101-103 UID channels: see Cay\.3 channels

spliceisoforms of, 391 , 393-395 UIE channels: see Cav2.3 channels C-terminus, 395 UIF channels: see Cav\.4 channels IVS3-IVS4extracellular linker, 391 UIG channels: see Cav3.! channels longintracellular domain II-III loop UIH channels: see Cav3.2 channels (Lu-III), 393-394 Un channels: see Cav3,3 channels Cav2.2 exon31a UIS channels: Ca.l .I channels dominant expression in peripheral neurons, see Chlordiazepoxide, 193 393 Climbing fiber-Purkinje cell (CF-PC), 315-316 Cav2.2 gene,structureof human,392 2 Conductance ofT-type Ca + currents,185 Ca .2 knockout mice v2 Congenital stationary nightblindness (CSNB), abnormal emotional statein, 285 308,312 abnormal pain responses in, 285-287 Conotoxin GS, 151 alteredsympathetic functions in, 284-285 N-typecurrentis missingin, 284 rc-conotcxin inhibition effectsof non-pore domainson, 121-122 Cav2.3 (R-type) channels, 103, 188,287-293 spliceisoforms of, 395-396 effectson mutations at pore domainon, 118-120 414 INDEX o>-conotoxin-MVlIA: see o>-CTx-MVIIA Cysteine string protein (CSP), 352 (o>-conotoxin-MVlIA) to-conotoxlns, 107 Dendroaspis polylepis polylepis(black mamba), affinity for partially inactivated vs. 116,148 noninactivated Ca.2.2 N-type IA-Dihydropyridine binding channels, 121 correlates with potency, 53 flexibility , folding and stability, IS1-153 in polarized and polarized cells, 52 independent binding of gating modifier toxins lA-Dihydropyridine block ofT-type calcium and, 115-116 channels, 45 structure-function relationships , 153-155 1A-Dihydropyridine calcium channel antagonists, 2 that block ea + channels, sequence alignment structural formulae of, 24 of,I44-145 1A-Dihydropyridine function, individual residues three-dimensional structures, 149-151 critical for, 41-42 amino acid sequence diversity, 149 1,4-Dihydropyridine(s), 28 Conus catus, 122 activator and antagonist properties of 4-(2­ Conusmagus, 149 pyridyl)-substituted, 38 Conusmarmoreus, 107 interactions with N- and P/Q-type channels, Conuspennaceus, 107 47 Conustextile, 107 interactions with T-type channels, 46 Cortisol,215-216 partition coefficients,SI CREB (cyclic AMP response element binding ring planarity and drug potency, 37 protein) , 245-250 state-dependent interactions, SO-53 CREB binding protein (CBP), 246 vascular:cardiac selectivity, 38 CREB response element (CRE), 246 Dihydropyrimidines (DHPs), 36, 104,381 CSP proteins, 241 action, 14-15 o>-CTx-CVID,149, ISS, 162-163 channel residues critical for, 41 for treatment of neuropathic pain, 163-165 isomers, 37 o>-CTx-GVIA (o>-conotoxin-GVIA), 101:"103, molecules used to measure binding site, 35 122, 151, 160-163 structure, 40 barium slows block by, 108 Diltiazem (DIL) action, 13-14 K2-YI3-R-17 GVIA pharmacophore, 157 Disulfide bonds in peptide toxins, 152-153 putative mimetics , 167, 168 Dopamine, 203-204 structure and structure-function relationships, Dopaminergic receptors, D., 348 151, 153-157 Dorsal root ganglia (DRG), 288 for treatment of neuropathic pain, 163-165 Drosophila, 105, 107,373-374 o>-CTx-GVIA binding, 108, I09-IlO mutations in, 322 calcium inhibits, 108, 109 Drug action, molecular mechanisms of, 13-15 Drug-inactivation synergism model, 10, 11, IS oo-CTx-GVIAinhibition, 119 Drugs, distinct receptor sites for different, 40 ofCa.2.2 channels, 121 location of residues whose mutation ducky(du) mutation and the (X20 gene (Cacna2d), affects kinetics of, 120 318 multiple domains contributing to speed of, Dystonia, 282 118 Ear hair cells, inner, 279-280 o>-CTx-GVIA-sensitive channels, 105-106 Electrophorus electricus eel, 109 o>-CTx-MVIIA (oo-conotoxin-MVIIA), 101-102, Endocrine cells, 200 121,122 Endothelin-l, 202-203 structure, structure-function , and structure­ Enflurane, 193 activity relationships , 149, Epilepsy, 311, 319 152-157, 162-163 absence, 317 for treatment of neuropathic pain, 163-165 Epileptic disorders, 213 o>-CTx-MVIIC (o>-conotoxin-MVIIC), 100-102, Epileptic seizures, 317-319 149,399,400 Episodic ataxia type 2 (EA-2), 306, 307, 311, 313 sensitivities of splice forms of Ca.2.1 to, 387 Estrogen, 200 structure and structure-function relationships , Ethosuximide , 191 154,156 Excitation-contraction (E-C) coupling, 294-295, CVID: see o>-CTx-CVID 306 Cyclic AMP response element binding protein: Excitatory postsynaptic current (EPSC), 315-316 see CREB Cys framework , 150-151 . INDEX 415

Excitatorypostsynaptic potentials(EPSPs),248, Heartcontraction,embryonic 283 CavI.2 channeland, 278 ExpressedSequenceTag (EST)databases,374 HippocampalCAl region, 242-244

Hippocampal function, Cav2.3 channeland, Facilitation, 204 290--291 Familialhemiplegicmigraine(FHM),306, Hololena curtatoxin (HoTX), 105 310--311 Hydantoinantiepilepticdrugs, 191-192 Fast afterhyperpolarization (fAHP), 254 Hypercholesterolemia. 212 Fear conditioningand memory, 290 Hyperpolarizations, 254-255 Field excitatorypostsynaptic potentials(fEPSPs), Hypertension, 209, 210 283.290 Hypokalemic periodicparalysis(HypoPP), Filistatahibemalis, 146, 147 304-306 Fluodipine,38, 40 Hysterocrates gigas, 146, 147

G proteincoupledreceptorkinases (GRKs),353 I-stateinhibitionmodel: see Slowinactivation G protein-coupled receptors(GPCRs), 331-333, model 354 IK channels,253-254 desensitization, 352-353 "Inactivated channelblock" model,8-9 dirner- or oligomerization, 353-354 Inhibitorcystineknot (ICK), 150--15 I ligandbinding, 335 Innerear hair cells (IHCs), 279-280 modulationofVDCCs by, 337-347 Insectcalciumchannels, 105-107 putativeGPCRsecondarystructure, 333 Insulin,2I6 G proteins,333-334 Insulin-like growthfactor I (IGF\).207 GPCRactivationof heterotrimeric, 335-336 Ischemia, cerebral modulatecalciumchannels,348 Cav2.2 channeland, 78-79 convergence of cell signalingat Cav2.3 channeland, 291 presynapticcalciumchannels, Isoflurane, 193 351-352 Isoproterenol, 199 Gn and voltage-independent inhibition, Isradipine, 12 348-349 KCNN4gene, 253 G!3y targetspresynapticcalciumchannels, Knockoff, 113 349-351 KP4,I59 Gabapentin,43,84-85 Kurtoxin,147-148 Gallopamil, 11 binding sites for, 127-128 Gating modifiertoxins on calciumchannelsof nativeneurons, 115 binding sites, 124-128 on clonedT-typechannels, I 15 independent binding, 115-116 subtype-specific alterationof gating, 114-115 Gene expression, 250--251 ; see also specificgenes L-typechannel-mediatedchangesin, 250 Glucocorticoids, 200 L-typechannels;see alsoCa.l (L-type)channels Glucosehomeostasis, Cav2.3 channeland. class and subclassof calciumchannel 292-293 activated, 50 Glucose-stimulatedinsulin secretion (GSlS),292, and gene expression, 245-251 293 significanceof link between, 248 GI326P, point mutation,119 influencinglong-termpotentiation/depression Grammostolaspatulata, 146. 147 and memory, 242-244 w-Grammotoxin SIA (grammotoxin), 147 linkingthem to transcription factors, 249-250 bindingsites for. 127-128 modeof cellular calciummobilization, 49 and depolarizingshiftsin activation voltage, pharmacokinetic factors.49-50 112-114 state-dependent interactions. 50--53 structure, 147, 157, 158 Laminin C4!32YI (Iaminin-9), 242 Growthhormonereleasinghormone(GHRH). lethargic(lh) mice, 315, 319 200 lethargic(lh) mutationand the !3. gene(Cacnb4). GVIA: see w-CTx-GVIA (w-conotoxin-GVIA) 318-319 LFA-1 antagonists, 167 Hadronyche infensa, 106 Localizedcalciumsignaling,249 Hadronyche versuta, 106, 147 Locustamigratoria, 148, 158-159 Hair cells, auditory,279-280 Long-termdepression(LTD), 242-244, 297 Halothane,193 Long-termpotentiation(LTP),242-244, 290 416 INDEX

2 Low-voltage-activated (LVA) Ca + currents, 184, Octanol, 193 291-292 Omega-conotoxins: see to-conotoxins Lymnaea stagnalis, 107 Open channel block, 2, 5 Open channel block model, 7-9 Macrosites for toxin inhibition, 117 Opioids, 203 MaxiK channels : see BK channels Outer hair cells (OHCs), 280 Medium afterhyperpolarization (mAHP), 254, 255

Memory, 242-244, 290 P-type (P/Q-type) channels: see Cav2.1 channels Metabotropic glutamate receptor I (mGluRI), 348 Pain, 80, 163-164

Mibefradil, 388 function of Cav2.3 channel in transmission of, and Cav3 channels, 190-191 289 2 and T-type Ca + channels, 207, 209, 210, Cav2.2 channel in treatment of, 74-78, 213-215 163-165 use-dependent block of Cav2.1 channels by, 2, Pain responses, abnormal, 285-287 3 Pancreatic f} cells, postnatal generation of Mibefradil action requires Cavl .3 channel, 280-281 PAA, D1L,and, 13-14 Parabuthus transvaalicus, 189 Microsites for toxin inhibition, 117 Parallel fiber-Purk inje cell (PF-PC) synapse, 315 Migraine , 81-83, 306, 310-311 PDZ interaction sequence, 249 Mitogen-activated protein kinase (MAPK), 352 Peirates turpis(assassin bug), 148, 159 Modulated receptor hypothesis, I, 2 Penfluridol, 194 Modulated receptor model, 10, 42 Peptide and protein blockers of calcium channels, Molluscan calcium channels, 107 143-148 Morphine, 163-165,214 Peptide toxin inhibition of voltage-gated calcium MrVIA and MrVIB , 107 channels, 95-96 Muscarinic agonists, 201-202 future directions , 130 Muscle (lIs channel, skeletal (seeCa.LI) mechanisms of inhibition, 107-108 HypoPP mutations in, 304, 305 alteration of channel voltage dependence, Mutations/mutant channels, 117-121 ,303-304, 110-117 323 inhibition of permeation, 108-110 in humans, 304-314 toxin selectivity among calcium channel in mice, 309, 321 subtypes, 97-107 auxiliary subunit mutations, 318-321 Peptide toxins, 32-33,189-190 mechanisms underlying neurological Phenobarbital, 191 phenotypes,321-322 Phenylalkylamines (PAAs), 28 tottering mouse strains and alA (Ca, 2.1) action, 13-14 mutations, 312, 314-318 individual residues critical for, 42 in non-mammals, 322-323 Phenytoin, 191, 193 Myocardium, 207 Phoneutria nigriventer (Brazilian armed spider), Myocytes, 200 145, 146 Pimozide, 194 N-methyl-D-aspartate (NMDA), 243-244 Plasticity, neuronal, 242-245 N-type channels: see Cav2 .2 (N-type) channels Platelet-derived growth factor (POOF), 206-207 Neuronal firing, repetitive, 212-214 Plectreurys tristes (PLTX), 105, 147 Neuronal plasticity , 242-245 PMP-D2, 158-159 Neurontin : see Gabapentin Polyglutamine(polyQ)in calciumchannels, 311-312 Neurotransrnission, 238-241 , 296 Polypeptides , calcium channel blocking, 143, 172 adaptor proteins, structural components of molecular mimicry of active zone, and, 241-242 background, 166-167 Nickel (Ni2+), 189 GVIA mimetics as potential therapeutics, Nicotinic acetylcholine receptors (nAChRs), 108 168-171 Nifedipine , 40 prospects for toxin mimetics, 171 Nitric oxide (NO), 297 rational design of GVIA mimetics, Nitrous oxide (N20 ), 193 167-168 Nociceptin, 203 pharmacological assays and therapeutic Nociception, 214 applications, 160-162 Norepinephrine, 201, 296-297 analgesia, 163-165 Nuclear factor of activated T-cells (NFATc), structure-activity relationships, 162-163 246-247,249,250 Pore vestibule of calcium channels, 108-110 INDEX 417

"Port" space of 1,4-dihydropyridines, 36 Spiders, 146; see also Snakes, spiders, and others Potassium channels, calcium-activated, 251-254 funnel-web, 105, 106, 145 calcium channels and, 255-256 Spike-and-wave discharges (SWDs), 294 functions in neurons , 254-255 Spinocerebellar ataxia type 6 (SCA 6), 307, 311, properties, 252 312,314 pharmacology , 252 Splice forms, 39, 126-127; see also Alternative Protein kinase (PKA), 199,202,348 splicing Protein kinase C (PKC), 348-349, 351 "Starboard" space of IA-dihydropyridines, 36 Protein synthesis, regulation of, 250-251 stargazer (stg)mutation and the y2 gene Plul, 157, 159 (Cacng2),319-321 Purkinje neurons, 314-318 State-dependent binding, structural basis of, 43 State-dependent channel inhibition , 7-10 Q-type channels, 126, 127; see also Cav2.1 State-dependent drug action, 7-11 channels drug-inactivation synergism , 11-13 Steroidogenesis, 207 R-state dependent inhibition, 7 Stroke, treatment of, 78-79 R-type channels: seeCav2.3 (R-type) channels Substance P, 202 2 R-type Ca + currents and associated channel Subunit(s) of calcium channel proteins, 187-188 a" 44; see also underAlternative splicing Receptor concepts, 10 gene tree, 370 Renal function, 209 knocking out, 277-294 RIM binding proteins (RBPs), 241 alA, 306-309, 312 RollingNagoya (tgrol) mice, 314-317 ale: see Calmodulin; Cav\.2 channels alF, 308, 312 Saccharomyces cerevisiae,322 ~,44 toxins, 147-148, 158 ~" 2 294-295 Secretory cells, Ca + currents in, 195-1% ~2,295-296,398-399 Segestria florentina, 146, 147 ~3, 296-297 Seizures; see also Epilepsy ~4,39~OO absence, 294, 317 y" 297-298 Selenocosmia huwena, 147 knockouts of, 294-298 Serotonin, 202 Supporting (ancillary) subunit a20, 43-44 Sevoflurane, 193 molecules that interact at, 43 ShK toxin, 169 SVIB,149 Sinatrial (SA) node, 280 Synaptic depression : see Long-term depression Sipatrigine , 193 Synaptic proteins, calcium channel interactions SK (small conductance) channels, 254, 255 with,239-241 Slow afterhyperpolarization (sAHP), 254-255 Synaptic transmission, 248 Slow inactivation hypothesis, 2 in Ca .1 knockout mice, 283 Slow inactivation model, 8-10 v2 Synaptotagmins, 240 Smooth muscle cells, 39,195 Syntaxin lA/B, 239, 240, 251, 352 Snake toxins, 148, 158; see alsospecifictoxins Snakes and spiders, peptide toxins from structure-function relationships, 159-160 Tactile allodynia, 163-165 three-dimensional structures, 155-159 Tetraethylammonium (TEA), 243 SNAP-25, 239, 240 (TTX), 290 SNARE complex (soluble NSF attachment protein tg (tottering) mice, 314-317 receptors),239-240 tg" mice, 316, 317 SNX-lll: see oo-CTx-MVlIA (m-conotoxin­ tg,l'mice, 316 rol MVllA) tg (rolling Nagoya) mice, 314-317 SNX-325, 147 Thalamocortical neuron firing, 212-213 SNX-482, 103,288 Theta-burst stimulation (TBS), 290 binding sites for, 127-128 Torpedo califomica , 242 and depolarizing shifts in activation voltage, tottering (tg) mouse strains and alA (Ca, 2.1) 112-114 mutations, 312, 314 Somatostatin, 203, 351 characterization of tottering mutants,

Sperm function, Cav2.3 channel and, 291-292 314-316 Spider , 105-106, 147; see also Peptide P-type channel function and neurological toxin inhibition ; specifictoxins phenotypes, 317-318 418 INDEX

Toxin binding sites on calcium channels, 117-118 Valproic acid, 193 binding sites of gating modifier toxins, Vascular pacemaking, 212 124-128 Vascular tone, 210 m-conotoxins as pore blockers, 118--122 Vasoactive intestinal peptide (VIP), 200 macrosite for oo-Aga-1l1A and DW13.3, Visual pathway development in fh subunit 123-124 knockoutrrrlce, 297 toxins sharing oo-conotoxinmacrosite, Voltage dependence, 184-185 122-123 Voltage-gated calcium channels; seealso Toxins ; see alsoPeptide toxin inhibition ; specific Alternative splicing; Peptide toxin toxins inhibition of voltage-gated calcium experimental use, 129 channels factors influencing potency, 129 auxiliary subunits, 398-400 that inhibit calcium channels, structural diversity among, 369-379; seealso 104-107 Alternative splicing; Subunit(s) of Transcription factors, linking L-type channels to, calcium channel, Ct.) 249-250 multiple genes, 371 TVIIA,151 TxVII, 149-150, 155 Yeast, 322-323 Tyrosine hydroxylase (TIl), 316 Tyrosine kinase (TK), 352 Ziconotide: see (J)-Cfx-MVIIA (co-conotoxin­ MVIIA) Use-dependent channel block, 2, 5-7,11,13 Zonisarnide, 193 quantitative analysis of, 3-5 Ustilago maydis, 159