Pharmacological inhibition of TRPM4 hyperpolarizes vascular smooth muscle

Author:

Gonzales Albert L.1,Garcia Zarine I.1,Amberg Gregory C.1,Earley Scott1

Affiliation:

1. Vascular Physiology Research Group, Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado

Abstract

The contractile state of vascular smooth muscle cells is regulated by small changes in membrane potential that gate voltage-dependent calcium channels. The melastatin transient receptor potential (TRP) channel TRPM4 is a critical mediator of pressure-induced membrane depolarization and arterial constriction. A recent study shows that the tricyclic compound 9-phenanthrol inhibits TRPM4, but not the related channel TRPM5. The current study investigated the specificity of 9-phenanthrol and the effects of the compound on pressure-induced smooth muscle depolarization and arterial constriction. Patch-clamp electrophysiology revealed that 9-phenanthrol blocks native TRPM4 currents in freshly isolated smooth muscle cells in a concentration-dependent manner (IC50 = 10.6 μM). 9-Phenanthrol (30 μM) had no effect on maximum evoked currents in human embryonic kidney cells expressing recombinant TRPC3 or TRPC6 channels. Large-conductance Ca2+-activated K+, voltage-dependent K+, inwardly rectifying K+, and voltage-dependent Ca2+ channel activity in native cerebral artery myocytes was not altered by administration of 9-phenanthrol (30 μM). Using intracellular microelectrodes to record smooth muscle membrane potential in isolated cerebral arteries pressurized to 70 mmHg, we found that 9-phenanthrol (30 μM) reversibly hyperpolarized the membrane from ∼−40 mV to ∼−70 mV. In addition, we found that myogenic tone was reversibly abolished when vessels were exposed to 9-phenanthrol. These data demonstrate that 9-phenanthrol is useful for studying the functional significance of TRPM4 in vascular smooth muscle cells and that TRPM4 is an important regulator of smooth muscle cell membrane depolarization and arterial constriction in response to intraluminal pressure.

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3