Journal Article

Kv2.1 channels play opposing roles in regulating membrane potential, Ca2+ channel function, and myogenic tone in arterial smooth muscle

McKinnon, David, Guarina, Laura, Rosati, Barbara, Klug, Nicholas R., Palacio, Stephanie, O’Dwyer, Samantha C., Trimmer, James S., Santana, L. Fernando, Matsumoto, Collin, Tajada, Sendoa

2020

Overview

SignificanceOur data challenge the generally accepted view that Kv2.1 proteins regulate arterial smooth muscle function by regulating their membrane potential. Rather, we discovered that Kv2.1 plays both conductive and structural roles with opposing functional consequences on arterial myocytes, with the former predominating in males, the latter in females. Opening of Kv2.1 channels opposes vasoconstriction by inducing membrane hyperpolarization. In addition to this conductive function, Kv2.1 promotes the structural clustering of CaV1.2 channels, thereby enhancing Ca2+ influx and inducing vasoconstriction. These two functions are highlighted by differences in the regulation of membrane potential, intracellular Ca2+, and myogenic tone between males and females. Our data suggest that these disparities derive from sex-specific variations in Kv2.1 expression levels in male versus female myocytes. The accepted role of the protein Kv2.1 in arterial smooth muscle cells is to form K+ channels in the sarcolemma. Opening of Kv2.1 channels causes membrane hyperpolarization, which decreases the activity of L-type CaV1.2 channels, lowering intracellular Ca2+ ([Ca2+]i) and causing smooth muscle relaxation. A limitation of this model is that it is based exclusively on data from male arterial myocytes. Here, we used a combination of electrophysiology as well as imaging approaches to investigate the role of Kv2.1 channels in male and female arterial myocytes. We confirmed that Kv2.1 plays a canonical conductive role but found it also has a structural role in arterial myocytes to enhance clustering of CaV1.2 channels. Less than 1% of Kv2.1 channels are conductive and induce membrane hyperpolarization. Paradoxically, by enhancing the structural clustering and probability of CaV1.2–CaV1.2 interactions within these clusters, Kv2.1 increases Ca2+ influx. These functional impacts of Kv2.1 depend on its level of expression, which varies with sex. In female myocytes, where expression of Kv2.1 protein is higher than in male myocytes, Kv2.1 has conductive and structural roles. Female myocytes have larger CaV1.2 clusters, larger [Ca2+]i, and larger myogenic tone than male myocytes. In contrast, in male myocytes, Kv2.1 channels regulate membrane potential but not CaV1.2 channel clustering. We propose a model in which Kv2.1 function varies with sex: in males, Kv2.1 channels control membrane potential but, in female myocytes, Kv2.1 plays dual electrical and CaV1.2 clustering roles. This contributes to sex-specific regulation of excitability, [Ca2+]i, and myogenic tone in arterial myocytes.

• Publisher: National Academy of Sciences
• Subject: 60 APPLIED LIFE SCIENCES / BASIC BIOLOGICAL SCIENCES / Biological Sciences / Calcium (intracellular) / calcium channel clustering / Calcium channels / Calcium channels (L-type) / Calcium channels (voltage-gated) / Calcium influx / Calcium ions / Channels / Clustering / Electrophysiology / Excitability / Hyperpolarization / Membrane potential / Membranes / Muscle contraction / Muscles / Myocytes / Physiology / Potassium channels (voltage-gated) / Proteins / Roles / Sarcolemma / Sex / Smooth muscle / voltage-gated calcium channels / voltage-gated potassium channels