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

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 Ca_V1.2 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 Ca_V1.2 channels. Less than 1% of Kv2.1 channels are conductive and induce membrane hyperpolarization. Paradoxically, by enhancing the structural clustering and probability of Ca_V1.2-Ca_V1.2 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 Ca_V1.2 clusters, larger [Ca²⁺]_i, and larger myogenic tone than male myocytes. In contrast, in male myocytes, Kv2.1 channels regulate membrane potential but not Ca_V1.2 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 Ca_V1.2 clustering roles. This contributes to sex-specific regulation of excitability, [Ca²⁺]_i, and myogenic tone in arterial myocytes.

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