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 mamba (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 Calciseptine, 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 toxins, 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 toxin 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-conotoxin affinityfor partiallyinactivated UIA channels: see Cav2.1 channels vs. noninactivated, 121 UIB channels: see Cav2.2 channels potencyand selectivity of co-conotoxins 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