Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text PDF (Full Text) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JGP Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lyashchenko, A. K. Articles by Tibbs, G. R. Search for Related Content PubMed PubMed Citation Articles by Lyashchenko, A. K. Articles by Tibbs, G. R. Social Bookmarking                      What's this?

¹ Department of Anesthesiology and ² Department of Pharmacology, Columbia University, New York, NY10032

Correspondence to Gareth R. Tibbs: GRT1{at}columbia.edu

I_H pacemaker channels carry a mixed monovalent cation current that, under physiological ion gradients, reverses at –34 mV, reflecting a 4:1 selectivity for K over Na. However, I_H channels display anomalous behavior with respect to permeant ions such that (a) open channels do not exhibit the outward rectification anticipated assuming independence; (b) gating and selectivity are sensitive to the identity and concentrations of externally presented permeant ions; (c) the channels' ability to carry an inward Na current requires the presence of external K even though K is a minor charge carrier at negative voltages. Here we show that open HCN channels (the hyperpolarization-activated, cyclic nucleotide sensitive pore forming subunits of I_H) undergo a fast, voltage-dependent block by intracellular Mg in a manner that suggests the ion binds close to, or within, the selectivity filter. Eliminating internal divalent ion block reveals that (a) the K dependence of conduction is mediated via K occupancy of site(s) within the pore and that asymmetrical occupancy and/or coupling of these sites to flux further shapes ion flow, and (b) the kinetics of equilibration between K-vacant and K-occupied states of the pore (10–20 µs or faster) is close to the ion transit time when the pore is occupied by K alone (0.5–3 µs), a finding that indicates that either ion:ion repulsion involving Na is adequate to support flux (albeit at a rate below our detection threshold) and/or the pore undergoes rapid, permeant ion-sensitive equilibration between nonconducting and conducting configurations. Biophysically, further exploration of the Mg site and of interactions of Na and K within the pore will tell us much about the architecture and operation of this unusual pore. Physiologically, these results suggest ways in which "slow" pacemaker channels may contribute dynamically to the shaping of fast processes such as Na-K or Ca action potentials.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Vemana, S. Pandey, and H. P. Larsson Intracellular Mg2+ is a voltage-dependent pore blocker of HCN channels Am J Physiol Cell Physiol, August 1, 2008; 295(2): C557 - C565. [Abstract] [Full Text] [PDF]

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents