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Titolo:
Regulation of hyperpolarization-activated HCN channel gating and cAMP modulation due to interactions of COOH terminus and core transmembrane regions
Autore:
Wang, J; Chen, S; Siegelbaum, SA;
Indirizzi:
Columbia Univ, Ctr Neurobiol & Behav, Howard Hughes Med Inst, New York, NY10032 USA Columbia Univ New York NY USA 10032 ughes Med Inst, New York, NY10032 USA Columbia Univ, Dept Pharmacol, Howard Hughes Med Inst, New York, NY 10032 USA Columbia Univ New York NY USA 10032 ghes Med Inst, New York, NY 10032 USA Columbia Univ, Integrated Program Cellular Mol & Biophys Studies, Howard Hughes Med Inst, New York, NY 10032 USA Columbia Univ New York NY USA 10032ghes Med Inst, New York, NY 10032 USA
Titolo Testata:
JOURNAL OF GENERAL PHYSIOLOGY
fascicolo: 3, volume: 118, anno: 2001,
pagine: 237 - 250
SICI:
0022-1295(200109)118:3<237:ROHHCG>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
NUCLEOTIDE-GATED CHANNELS; PACEMAKER CHANNELS; K+-CHANNEL; CLONING; NEURONS; FAMILY; DOMAIN; HEART; BRAIN;
Keywords:
pacemaker channel; I-h; potassium channel; cyclic nucleotide; chimera;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
27
Recensione:
Indirizzi per estratti:
Indirizzo: Siegelbaum, SA Columbia Univ, Ctr Neurobiol & Behav, Howard Hughes Med Inst, 722 W 168 St, New York, NY 10032 USA Columbia Univ 722 W 168 St New YorkNY USA 10032 10032 USA
Citazione:
J. Wang et al., "Regulation of hyperpolarization-activated HCN channel gating and cAMP modulation due to interactions of COOH terminus and core transmembrane regions", J GEN PHYSL, 118(3), 2001, pp. 237-250

Abstract

Members of the hyperpolarization-activated cation (HCN) channel family generate HCN currents (I-h) that are directly regulated by cAMP and contributeto pacemaking activity in heart and brain. The four different HCN isoformsshow distinct biophysical properties. In cell-free patches from Xenopus oocytes, the steady-state activation curve of HCN2 channels is 20 mV more hyperpolarized compared with HCN1. Whereas the binding of cAMP to a COOH-terminal cyclic nucleotide binding domain (CNBD) markedly shifts the activation Curve of HCN2 by 17 mV to more positive potentials, the response of HCN1 ismuch less pronounced (4 mV shift). A previous deletion mutant study suggested that the CNBD inhibits hyperpolarization-gating in the absence of cAMP;the binding of cAMP shifts gating to more positive voltages by relieving this inhibition. The differences in basal gating and cAMP responsiveness between HCN1 and HCN2 were proposed to result from a greater inhibitory effectof the CNBD in HCN2 compared with HCN1. Here, We use a series of chimeras between HCN1 and HCN2, in which we exchange the NH2, terminus, the transmembrane domain, or distinct domains of the COOH terminus, to investigate further the molecular bases for the modulatory action of cAMP and for the differences in the functional properties of the two channels. Differences in cAMP regulation between HCN1 and HCN2 are localized to sequence differences within the COOH terminus of the two channels. Surprisingly, exchange of the CNBDs between HCN1 and HCN2 has little effect on basal gating and has only amodest one on cAMP modulation. Rather, differences in cAMP modulation depend on the interaction between the CNBD and the C-linker, a conserved 80-amino acid region that connects the last (S6) transmembrane segment to the CNBD. Differences in basal gating depend on both the core transmembrane domainand the COOH terminus. These data, taken in the context of the previous data on deletion mutants, suggest that the inhibitory effect of the CNBD on basal gating depends on its interactions with both the C-linker and core transmembrane domain of the channel. The extent to which cAMP binding is able to relieve this inhibition is dependent on the interaction between the C-linker and the CNBD.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/07/20 alle ore 14:45:33