Sixtransmembrane one-porechannelsPoreandselectivityfilterThetripeptidesequencemotifG(Y/F)GlocatedintheS5-S6linkeriscommontotheporeorP-loopoftheseandotherK+channels and hence is considered asthe K+-selectivitysignaturemotif.Theexternal entry tothe channel pore consisting of portionsoftheP-loopandadjacentresiduesinbothS5andS6segments constitutes bindingsitesfor toxins and Kt channelblockers.TheinternalvestibuleofporecomposedofresiduesfromS5andS6segmentsfacingthe intracellularside contributestobindingsitesforcompoundssuchas4-aminopyridinetetraethylammonium,and quinidine.TheS4-S5linkerliesclosetothepermeationpathwayandformspartofthereceptorfortheinactivationball
Six transmembrane one-pore channels Pore and selectivity filter The tripeptide sequence motif G(Y/F)G located in the S5-S6 linker is common to the pore or P-loop of these and other K+ channels and hence is considered as the K +-selectivity signature motif. The external entry to the channel pore consisting of portions of the P-loop and adjacent residues in both S5 and S6 segments constitutes binding sites for toxins and K+ channel blockers. The internal vestibule of pore composed of residues from S5 and S6 segments facing the intracellular side contributes to binding sites for compounds such as 4-aminopyridine, tetraethylammonium, and quinidine. The S4-S5 linker lies close to the permeation pathway and forms part of the receptor for the inactivation ball
Six transmembrane one-pore channelsVoltagesensorandchannelactivationInvoltage-dependentionchannels,membranedepolarizationis reguired to cause conformational changes leading tochannel opening,whichallowspermeantionsto flow.ThetransmembraneS4segmentrepresentsthemajorcomponent of the voltagesensor.TheS4 segment thatcontains positively charged residues (lysine orarginine)atapproximatelyeverythird positionresultinginaregularlyspacedarrayof5to7positivechargesisconservedwithinthevoltage-gatedK+channelfamilyInactivation·Many voltage-dependent K+ channels activate and inactivaterapidlywhen membrane potential becomesmorepositive.Inactivation is a nonconductingstate duringmaintaineddepolarization. Three types of inactivation,i.e.,N-,P-,and C.type, have been characterized and associated with distinctmoleculardomainsofthechannelSubunit interactionand assembly domains
Six transmembrane one-pore channels Voltage sensor and channel activation In voltage-dependent ion channels, membrane depolarization is required to cause conformational changes leading to channel opening, which allows permeant ions to flow. The transmembrane S4 segment represents the major component of the voltage sensor. The S4 segment that contains positively charged residues (lysine or arginine) at approximately every third position resulting in a regularly spaced array of 5 to 7 positive charges is conserved within the voltage-gated K+ channel family. Inactivation Many voltage-dependent K+ channels activate and inactivate rapidly when membrane potential becomes more positive. Inactivation is a nonconducting state during maintained depolarization. Three types of inactivation, i.e., N-, P-, and Ctype, have been characterized and associated with distinct molecular domains of the channel. Subunit interaction and assembly domains
Two transmembrane one-pore channelsInwardrectifierK+Kir1.1RomkchannelscontainingKir2.1IK,Kir3.1/Kir3.4lAChonlytwoKir6.2/SURKATPNH3transmembraneCOO:regionsandasingleporeloop inbetween.This inward rectification isattributed to gating mechanismsbyinternalMg2+andpolyamines(spermine,spermidine,etc.)thatoccludeaccessofK+totheinternalvestibuleofaconductingpore.They are important in settingthe restingmembranepotential
Two transmembrane one-pore channels This inward rectification is attributed to gating mechanisms by internal Mg2+ and polyamines (spermine, spermidine, etc.) that occlude access of K+ to the internal vestibule of a conducting pore. They are important in setting the resting membrane potential. Inward rectifier K+ channels containing only two transmembrane regions and a single pore loop in between
Fourtransmembranetwo-porechannelsTwo-poreK+channelsTWIKTREKcontaining fourTASKTRAAKtransmembraneswithtwoNH3poreregions.COOThey represent the most abundant class of K+ channels (at leastinC.elegans),with>50 distinct members.The G(Y/F)GresiduesofKt-selectivemotifispreservedinthefirstporeloop ofthetwo-poreK+channel,but itisreplacedbyGFGorGLGinthesecondporeloop.All thetwo-pore channels haveaconserved coreregionbetweentransmembrane segmentsM1 and M4.The amino-andcarboxyl-terminal domains are quite diverse.Two-pore domainsubunitswouldpresumably formachannelto retainthetetrameric arrangement
Four transmembrane two-pore channels They represent the most abundant class of K+ channels (at least in C. elegans), with >50 distinct members. The G(Y/F)G residues of K +-selective motif is preserved in the first pore loop of the two-pore K+ channel, but it is replaced by GFG or GLG in the second pore loop. All the two-pore channels have a conserved core region between transmembrane segments M1 and M4. The amino- and carboxyl-terminal domains are quite diverse. Two-pore domain subunits would presumably form a channel to retain the tetrameric arrangement. Two-pore K+ channels containing four transmembranes with two pore regions
AuxiliarysubunitsTheKv1channels associatewith cytoplasmicβ-subunitstoalterchannelkinetics.Chaperoneproteins,suchasKChAP,regulatingthefunctionandexpressionofsomeoftheKvchannels,suchasKv2.1,Kv1.3,andKv4.3,havebeenreported.CertainotherKvchannels,suchasKv5,Kv6,Kv8andKv9,donotformfunctionalchannelsthemselvesbutassociatewithKv2.1channelstoalterthebiophysicalproperties.Distinct β-subunits that associate with the calcium-activated Ktchannels,sulfonylurea receptors for the inward rectifiers Kir6.1orKir6.2,andminKandminK-relatedpeptides(MiRPs)forthecardiacdelayed rectifierchannels.Thesesubunitsplayrolesasdiverseasmodulationofgatingpropertiessuchasinactivation,cell surfaceexpression,and/ortrafficking oftheion channel complex,to serving asbindingsitesforboth endogenous and exogenous ligands.GiventhediversityofK+channel subunitsand thepotential to varytheconstituentstoformdiverseα-αorα-βheteromericchannelcomplexestoalterexpression,cellulartargeting,andbiophysicalandpharmacological properties in nativecell types.Understandingtheprecisecompositionofchannelcomplexesinvivoremainsachallenge
Auxiliary subunits The Kv1 channels associate with cytoplasmic -subunits to alter channel kinetics. Chaperone proteins, such as KChAP, regulating the function and expression of some of the Kv channels, such as Kv2.1, Kv1.3, and Kv4.3, have been reported. Certain other Kv channels, such as Kv5, Kv6, Kv8, and Kv9, do not form functional channels themselves but associate with Kv2.1 channels to alter the biophysical properties. Distinct -subunits that associate with the calcium-activated K+ channels, sulfonylurea receptors for the inward rectifiers Kir6.1 or Kir6.2, and minK and minK-related peptides (MiRPs) for the cardiac delayed rectifier channels. These subunits play roles as diverse as modulation of gating properties such as inactivation, cell surface expression, and/or trafficking of the ion channel complex, to serving as binding sites for both endogenous and exogenous ligands. Given the diversity of K+ channel subunits and the potential to vary the constituents to form diverse - or - heteromeric channel complexes to alter expression, cellular targeting, and biophysical and pharmacological properties in native cell types. Understanding the precise composition of channel complexes in vivo remains a challenge