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Use-dependent 'agonist' effect of azimilide on the HERG channel.
J Pharmacol Exp Ther. 1999 Dec; 291(3):1324-36.JP

Abstract

Azimilide (AZ) is a class III antiarrhythmic drug that has voltage-dependent dual effects on the HERG channel: 1) increasing current amplitude at low-voltage depolarization (agonist effect), and 2) suppressing current at more depolarized voltages (antagonist effect). We examined the mechanism for the agonist effect of AZ on HERG expressed in Xenopus oocytes. The agonist effect resulted from an AZ-induced 'prepulse potentiation: a strong depolarization prepulse increased the rate and degree of channel activation induced by subsequent depolarization to -50 or -40 mV. The potentiated state decayed slowly in an exponential fashion (time constant, 60-80 s). Degrees of potentiation were proportional to degrees of channel activation during prepulses; hence, the agonist effect of AZ was use dependent. AZ exerted its agonist effect from outside the cell membrane, and the effect did not depend on intracellular G-protein or protein kinase activity. Mutations made in the outer mouth or an extracellular loop connecting the S5 and P regions of HERG, which could hinder or modify conformational changes in the pore region during membrane depolarization, reduced or abolished AZ-induced prepulse potentiation. Importantly, these same mutations also increased the rate and degree of channel activation in the negative voltage range, and the degree of change in the activation properties was inversely correlated with the degree of AZ-induced prepulse potentiation. We propose that conformational changes in the outer mouth and neighboring extracellular domain of HERG during membrane depolarization can affect the process of channel activation. In the presence of AZ, channel activation allowed drug modification of these conformational changes, which subsequently facilitated HERG activation by low-voltage depolarization.

Authors+Show Affiliations

Department of Pharmacology, Columbia University, New York, New York, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10565858

Citation

Jiang, M, et al. "Use-dependent 'agonist' Effect of Azimilide On the HERG Channel." The Journal of Pharmacology and Experimental Therapeutics, vol. 291, no. 3, 1999, pp. 1324-36.
Jiang M, Dun W, Fan JS, et al. Use-dependent 'agonist' effect of azimilide on the HERG channel. J Pharmacol Exp Ther. 1999;291(3):1324-36.
Jiang, M., Dun, W., Fan, J. S., & Tseng, G. N. (1999). Use-dependent 'agonist' effect of azimilide on the HERG channel. The Journal of Pharmacology and Experimental Therapeutics, 291(3), 1324-36.
Jiang M, et al. Use-dependent 'agonist' Effect of Azimilide On the HERG Channel. J Pharmacol Exp Ther. 1999;291(3):1324-36. PubMed PMID: 10565858.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Use-dependent 'agonist' effect of azimilide on the HERG channel. AU - Jiang,M, AU - Dun,W, AU - Fan,J S, AU - Tseng,G N, PY - 1999/11/24/pubmed PY - 1999/11/24/medline PY - 1999/11/24/entrez SP - 1324 EP - 36 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 291 IS - 3 N2 - Azimilide (AZ) is a class III antiarrhythmic drug that has voltage-dependent dual effects on the HERG channel: 1) increasing current amplitude at low-voltage depolarization (agonist effect), and 2) suppressing current at more depolarized voltages (antagonist effect). We examined the mechanism for the agonist effect of AZ on HERG expressed in Xenopus oocytes. The agonist effect resulted from an AZ-induced 'prepulse potentiation: a strong depolarization prepulse increased the rate and degree of channel activation induced by subsequent depolarization to -50 or -40 mV. The potentiated state decayed slowly in an exponential fashion (time constant, 60-80 s). Degrees of potentiation were proportional to degrees of channel activation during prepulses; hence, the agonist effect of AZ was use dependent. AZ exerted its agonist effect from outside the cell membrane, and the effect did not depend on intracellular G-protein or protein kinase activity. Mutations made in the outer mouth or an extracellular loop connecting the S5 and P regions of HERG, which could hinder or modify conformational changes in the pore region during membrane depolarization, reduced or abolished AZ-induced prepulse potentiation. Importantly, these same mutations also increased the rate and degree of channel activation in the negative voltage range, and the degree of change in the activation properties was inversely correlated with the degree of AZ-induced prepulse potentiation. We propose that conformational changes in the outer mouth and neighboring extracellular domain of HERG during membrane depolarization can affect the process of channel activation. In the presence of AZ, channel activation allowed drug modification of these conformational changes, which subsequently facilitated HERG activation by low-voltage depolarization. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/10565858/Use_dependent_'agonist'_effect_of_azimilide_on_the_HERG_channel_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10565858 DB - PRIME DP - Unbound Medicine ER -