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An arginine residue in the pore region is a key determinant of chloride dependence in cardiac pacemaker channels.
J Biol Chem. 2005 Apr 08; 280(14):13694-700.JB

Abstract

The modulation of ion channel activity by extracellular ions plays a central role in the control of heart function. Here, we show that the sinoatrial pacemaker current I(f) is strongly affected by the extracellular Cl- concentration. We investigated the molecular basis of the Cl- dependence in heterologously expressed hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that represent the molecular correlate of I(f). Currents carried by the two cardiac HCN channel isoforms (HCN2 and HCN4) showed the same strong Cl- dependence as the sinoatrial I(f) and decreased to about 10% in the absence of external Cl-. In contrast, the neuronal HCN1 current was reduced to only 50% under the same conditions. Depletion of Cl- did not affect the voltage dependence of activation or the ion selectivity of the channels, indicating that the reduction of I(f) was caused by a decrease of channel conductance. A series of chimeras between HCN1 and HCN2 was constructed to identify the structural determinants underlying the different Cl- dependence of HCN1 and HCN2. Exchange of the ion-conducting pore region was sufficient to switch the Cl- dependence from HCN1- to HCN2-type and vice versa. Replacement of a single alanine residue in the pore of HCN1 (Ala-352) by an arginine residue present in HCN2 at equivalent position (Arg-405) induced HCN2-type chloride sensitivity in HCN1. Our data indicate that Arg-405 is a key component of a domain that allosterically couples Cl- binding with channel activation.

Authors+Show Affiliations

Department Pharmazie - Pharmakologie für Naturwissenschaften, Ludwig-Maximilians-Universität München, Butenandtstr. 7-13, 81377 München, Germany.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15644313

Citation

Wahl-Schott, Christian, et al. "An Arginine Residue in the Pore Region Is a Key Determinant of Chloride Dependence in Cardiac Pacemaker Channels." The Journal of Biological Chemistry, vol. 280, no. 14, 2005, pp. 13694-700.
Wahl-Schott C, Baumann L, Zong X, et al. An arginine residue in the pore region is a key determinant of chloride dependence in cardiac pacemaker channels. J Biol Chem. 2005;280(14):13694-700.
Wahl-Schott, C., Baumann, L., Zong, X., & Biel, M. (2005). An arginine residue in the pore region is a key determinant of chloride dependence in cardiac pacemaker channels. The Journal of Biological Chemistry, 280(14), 13694-700.
Wahl-Schott C, et al. An Arginine Residue in the Pore Region Is a Key Determinant of Chloride Dependence in Cardiac Pacemaker Channels. J Biol Chem. 2005 Apr 8;280(14):13694-700. PubMed PMID: 15644313.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An arginine residue in the pore region is a key determinant of chloride dependence in cardiac pacemaker channels. AU - Wahl-Schott,Christian, AU - Baumann,Ludwig, AU - Zong,Xiangang, AU - Biel,Martin, Y1 - 2005/01/10/ PY - 2005/1/13/pubmed PY - 2005/6/23/medline PY - 2005/1/13/entrez SP - 13694 EP - 700 JF - The Journal of biological chemistry JO - J Biol Chem VL - 280 IS - 14 N2 - The modulation of ion channel activity by extracellular ions plays a central role in the control of heart function. Here, we show that the sinoatrial pacemaker current I(f) is strongly affected by the extracellular Cl- concentration. We investigated the molecular basis of the Cl- dependence in heterologously expressed hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that represent the molecular correlate of I(f). Currents carried by the two cardiac HCN channel isoforms (HCN2 and HCN4) showed the same strong Cl- dependence as the sinoatrial I(f) and decreased to about 10% in the absence of external Cl-. In contrast, the neuronal HCN1 current was reduced to only 50% under the same conditions. Depletion of Cl- did not affect the voltage dependence of activation or the ion selectivity of the channels, indicating that the reduction of I(f) was caused by a decrease of channel conductance. A series of chimeras between HCN1 and HCN2 was constructed to identify the structural determinants underlying the different Cl- dependence of HCN1 and HCN2. Exchange of the ion-conducting pore region was sufficient to switch the Cl- dependence from HCN1- to HCN2-type and vice versa. Replacement of a single alanine residue in the pore of HCN1 (Ala-352) by an arginine residue present in HCN2 at equivalent position (Arg-405) induced HCN2-type chloride sensitivity in HCN1. Our data indicate that Arg-405 is a key component of a domain that allosterically couples Cl- binding with channel activation. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/15644313/An_arginine_residue_in_the_pore_region_is_a_key_determinant_of_chloride_dependence_in_cardiac_pacemaker_channels_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(19)60444-8 DB - PRIME DP - Unbound Medicine ER -