Not So Funny Anymore Pacing Channels Are Cloned

inward rectifier (Kir) class channels and low numbers of nonselective ion channels. In pacing neurons and cardiac cells, I f disturbs this equilibrium by gently nudging the membrane potential in the depolarizing direction. Although I f appears to be important in pacing in several Boston, Massachusetts 02115 excitable cell types, it is by no means the only type of current that controls pacemaker depolarization (Noma, 1996; Wickman et al., 1998). Rhythms are common in our lives. These repetitions If's small single channel conductance (1 pS; DiFran-of events over characteristic time intervals govern the cesco, 1986), low density, and control by numerous sig-beating of the heart, sleep cycles, and the release of nal transduction regulatory pathways allows cells to hormones. Not surprisingly, the first recognition of an finely tune firing rates. For example, sympathetic stimu-ion current controlling rhythmicity was discovered in lation doubles cardiac cell firing rate largely through in-heart, the most reliably periodic organ. Now, three creasing intracellular cAMP. Epinephrine binds ␤-adren-groups have cloned the genes responsible for pace-ergic receptors which activate G proteins and, in turn, maker currents (Gauss et al., 1998; Ludwig et al., 1998; adenylyl cyclase. This enzyme raises the level of intracel-Santoro et al., 1998). The pacing channel proteins turn lular cAMP, which presumably directly binds the CNG out to be cousins of voltage-gated K ϩ channels, and as region of the I f channel protein. As a result, I f activity expected, display properties of the cyclic nuceotide– increases and depolarization is accelerated. cAMP also gated nonselective channels, the plant inwardly rectify-activates protein kinase A, which phosphorylates volt-ing K ϩ channel, KAT1, and the mammalian HERG K ϩ age-dependent Ca 2ϩ channels and K ϩ channels, increas-channels. Although three separate names are proposed ing their activities, speeding depolarization, increasing for the channel, Hyperpolarization-Activated, Cyclic Nu-contractility, and shortening the action potential dura-cleotide-Gated K ϩ (HCN) seems an appropriate abbrevi-tion. The end result is a significant increase in heart rate ation. and contractility. Similar mechanisms for regulation by This discovery of pacemaker currents was not as G protein–linked receptors modulate repetitive firing straightforward as it might now seem in this age of rates in neurons (reviewed by Pape, 1996). The role of patch-clamp methodologies. The timing of the pace-cGMP in controlling pacing currents is intriguing but maker depolarization in heart was at first thought to less well understood. be controlled by a slow decline in conductance during …