External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor

Marcin Kazmierczak, Xiaofei Zhang, Bihan Chen, Daniel K. Mulkey, Yingtang Shi, Paul G. Wagner, Kendra Pivaroff-Ward, Jessica K. Sassic, Douglas A. Bayliss, Timothy Jegla

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The Ether-a-go-go (EAG) superfamily of voltage-gated K+ channels consists of three functionally distinct gene families (Eag, Elk, and Erg) encoding a diverse set of low-threshold K+ currents that regulate excitability in neurons and muscle. Previous studies indicate that external acidification inhibits activation of three EAG superfamily K+ channels, Kv10.1 (Eag1), Kv11.1 (Erg1), and Kv12.1 (Elk1). We show here that Kv10.2, Kv12.2, and Kv12.3 are similarly inhibited by external protons, suggesting that high sensitivity to physiological pH changes is a general property of EAG superfamily channels. External acidification depolarizes the conductance-voltage (GV) curves of these channels, reducing low threshold activation. We explored the mechanism of this high pH sensitivity in Kv12.1, Kv10.2, and Kv11.1. We first examined the role of acidic voltage sensor residues that mediate divalent cation block of voltage activation in EAG superfamily channels because protons reduce the sensitivity of Kv12.1 to Zn2+. Low pH similarly reduces Mg2+ sensitivity of Kv10.1, and we found that the pH sensitivity of Kv11.1 was greatly attenuated at 1 mM Ca2+. Individual neutralizations of a pair of EAG-specific acidic residues that have previously been implicated in divalent block of diverse EAG superfamily channels greatly reduced the pH response in Kv12.1, Kv10.2, and Kv11.1. Our results therefore suggest a common mechanism for pH-sensitive voltage activation in EAG superfamily channels. The EAG-specific acidic residues may form the proton-binding site or alternatively are required to hold the voltage sensor in a pH-sensitive conformation. The high pH sensitivity of EAG superfamily channels suggests that they could contribute to pH-sensitive K+ currents observed in vivo.

Original languageEnglish (US)
Pages (from-to)721-735
Number of pages15
JournalJournal of General Physiology
Volume141
Issue number6
DOIs
StatePublished - Jun 1 2013

Fingerprint

Ether
Protons
Voltage-Gated Potassium Channels
Divalent Cations
Binding Sites
Neurons
Muscles
Genes

All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

Kazmierczak, Marcin ; Zhang, Xiaofei ; Chen, Bihan ; Mulkey, Daniel K. ; Shi, Yingtang ; Wagner, Paul G. ; Pivaroff-Ward, Kendra ; Sassic, Jessica K. ; Bayliss, Douglas A. ; Jegla, Timothy. / External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor. In: Journal of General Physiology. 2013 ; Vol. 141, No. 6. pp. 721-735.
@article{cab0c582a8fd4e49bfe5e37881d49aee,
title = "External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor",
abstract = "The Ether-a-go-go (EAG) superfamily of voltage-gated K+ channels consists of three functionally distinct gene families (Eag, Elk, and Erg) encoding a diverse set of low-threshold K+ currents that regulate excitability in neurons and muscle. Previous studies indicate that external acidification inhibits activation of three EAG superfamily K+ channels, Kv10.1 (Eag1), Kv11.1 (Erg1), and Kv12.1 (Elk1). We show here that Kv10.2, Kv12.2, and Kv12.3 are similarly inhibited by external protons, suggesting that high sensitivity to physiological pH changes is a general property of EAG superfamily channels. External acidification depolarizes the conductance-voltage (GV) curves of these channels, reducing low threshold activation. We explored the mechanism of this high pH sensitivity in Kv12.1, Kv10.2, and Kv11.1. We first examined the role of acidic voltage sensor residues that mediate divalent cation block of voltage activation in EAG superfamily channels because protons reduce the sensitivity of Kv12.1 to Zn2+. Low pH similarly reduces Mg2+ sensitivity of Kv10.1, and we found that the pH sensitivity of Kv11.1 was greatly attenuated at 1 mM Ca2+. Individual neutralizations of a pair of EAG-specific acidic residues that have previously been implicated in divalent block of diverse EAG superfamily channels greatly reduced the pH response in Kv12.1, Kv10.2, and Kv11.1. Our results therefore suggest a common mechanism for pH-sensitive voltage activation in EAG superfamily channels. The EAG-specific acidic residues may form the proton-binding site or alternatively are required to hold the voltage sensor in a pH-sensitive conformation. The high pH sensitivity of EAG superfamily channels suggests that they could contribute to pH-sensitive K+ currents observed in vivo.",
author = "Marcin Kazmierczak and Xiaofei Zhang and Bihan Chen and Mulkey, {Daniel K.} and Yingtang Shi and Wagner, {Paul G.} and Kendra Pivaroff-Ward and Sassic, {Jessica K.} and Bayliss, {Douglas A.} and Timothy Jegla",
year = "2013",
month = "6",
day = "1",
doi = "10.1085/jgp.201210938",
language = "English (US)",
volume = "141",
pages = "721--735",
journal = "Journal of General Physiology",
issn = "0022-1295",
publisher = "Rockefeller University Press",
number = "6",

}

Kazmierczak, M, Zhang, X, Chen, B, Mulkey, DK, Shi, Y, Wagner, PG, Pivaroff-Ward, K, Sassic, JK, Bayliss, DA & Jegla, T 2013, 'External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor', Journal of General Physiology, vol. 141, no. 6, pp. 721-735. https://doi.org/10.1085/jgp.201210938

External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor. / Kazmierczak, Marcin; Zhang, Xiaofei; Chen, Bihan; Mulkey, Daniel K.; Shi, Yingtang; Wagner, Paul G.; Pivaroff-Ward, Kendra; Sassic, Jessica K.; Bayliss, Douglas A.; Jegla, Timothy.

In: Journal of General Physiology, Vol. 141, No. 6, 01.06.2013, p. 721-735.

Research output: Contribution to journalArticle

TY - JOUR

T1 - External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor

AU - Kazmierczak, Marcin

AU - Zhang, Xiaofei

AU - Chen, Bihan

AU - Mulkey, Daniel K.

AU - Shi, Yingtang

AU - Wagner, Paul G.

AU - Pivaroff-Ward, Kendra

AU - Sassic, Jessica K.

AU - Bayliss, Douglas A.

AU - Jegla, Timothy

PY - 2013/6/1

Y1 - 2013/6/1

N2 - The Ether-a-go-go (EAG) superfamily of voltage-gated K+ channels consists of three functionally distinct gene families (Eag, Elk, and Erg) encoding a diverse set of low-threshold K+ currents that regulate excitability in neurons and muscle. Previous studies indicate that external acidification inhibits activation of three EAG superfamily K+ channels, Kv10.1 (Eag1), Kv11.1 (Erg1), and Kv12.1 (Elk1). We show here that Kv10.2, Kv12.2, and Kv12.3 are similarly inhibited by external protons, suggesting that high sensitivity to physiological pH changes is a general property of EAG superfamily channels. External acidification depolarizes the conductance-voltage (GV) curves of these channels, reducing low threshold activation. We explored the mechanism of this high pH sensitivity in Kv12.1, Kv10.2, and Kv11.1. We first examined the role of acidic voltage sensor residues that mediate divalent cation block of voltage activation in EAG superfamily channels because protons reduce the sensitivity of Kv12.1 to Zn2+. Low pH similarly reduces Mg2+ sensitivity of Kv10.1, and we found that the pH sensitivity of Kv11.1 was greatly attenuated at 1 mM Ca2+. Individual neutralizations of a pair of EAG-specific acidic residues that have previously been implicated in divalent block of diverse EAG superfamily channels greatly reduced the pH response in Kv12.1, Kv10.2, and Kv11.1. Our results therefore suggest a common mechanism for pH-sensitive voltage activation in EAG superfamily channels. The EAG-specific acidic residues may form the proton-binding site or alternatively are required to hold the voltage sensor in a pH-sensitive conformation. The high pH sensitivity of EAG superfamily channels suggests that they could contribute to pH-sensitive K+ currents observed in vivo.

AB - The Ether-a-go-go (EAG) superfamily of voltage-gated K+ channels consists of three functionally distinct gene families (Eag, Elk, and Erg) encoding a diverse set of low-threshold K+ currents that regulate excitability in neurons and muscle. Previous studies indicate that external acidification inhibits activation of three EAG superfamily K+ channels, Kv10.1 (Eag1), Kv11.1 (Erg1), and Kv12.1 (Elk1). We show here that Kv10.2, Kv12.2, and Kv12.3 are similarly inhibited by external protons, suggesting that high sensitivity to physiological pH changes is a general property of EAG superfamily channels. External acidification depolarizes the conductance-voltage (GV) curves of these channels, reducing low threshold activation. We explored the mechanism of this high pH sensitivity in Kv12.1, Kv10.2, and Kv11.1. We first examined the role of acidic voltage sensor residues that mediate divalent cation block of voltage activation in EAG superfamily channels because protons reduce the sensitivity of Kv12.1 to Zn2+. Low pH similarly reduces Mg2+ sensitivity of Kv10.1, and we found that the pH sensitivity of Kv11.1 was greatly attenuated at 1 mM Ca2+. Individual neutralizations of a pair of EAG-specific acidic residues that have previously been implicated in divalent block of diverse EAG superfamily channels greatly reduced the pH response in Kv12.1, Kv10.2, and Kv11.1. Our results therefore suggest a common mechanism for pH-sensitive voltage activation in EAG superfamily channels. The EAG-specific acidic residues may form the proton-binding site or alternatively are required to hold the voltage sensor in a pH-sensitive conformation. The high pH sensitivity of EAG superfamily channels suggests that they could contribute to pH-sensitive K+ currents observed in vivo.

UR - http://www.scopus.com/inward/record.url?scp=84878606893&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878606893&partnerID=8YFLogxK

U2 - 10.1085/jgp.201210938

DO - 10.1085/jgp.201210938

M3 - Article

C2 - 23712551

AN - SCOPUS:84878606893

VL - 141

SP - 721

EP - 735

JO - Journal of General Physiology

JF - Journal of General Physiology

SN - 0022-1295

IS - 6

ER -