The formation of KV2.1 macro-clusters is required for sex-specific differences in L-type CaV1.2 clustering and function in arterial myocytes

• Published in: Communications biology 2023-11, Vol.6 (1), p.1165-21, Article 1165
• Main Authors: Matsumoto, Collin, O’Dwyer, Samantha C., Manning, Declan, Hernandez-Hernandez, Gonzalo, Rhana, Paula, Fong, Zhihui, Sato, Daisuke, Clancy, Colleen E., Vierra, Nicholas C., Trimmer, James S., Fernando Santana, L.
• Format: Article
• Language: English
• Subjects: 14; 14/1; 14/19; 14/35; 631/443/592; 692/4019/592; 9/74; Biology; Biomedical and Life Sciences; Calcium channels (voltage-gated); Channel gating; Depolarization; Dihydropyridine; Electrophysiology; Life Sciences; Membrane potential; Myocytes; Phosphorylation; Potassium channels (voltage-gated); Sex; Smooth muscle
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-05527-1

In arterial myocytes, the canonical function of voltage-gated Ca V 1.2 and K V 2.1 channels is to induce myocyte contraction and relaxation through their responses to membrane depolarization, respectively. Paradoxically, K V 2.1 also plays a sex-specific role by promoting the clustering and activity of Ca V 1.2 channels. However, the impact of K V 2.1 protein organization on Ca V 1.2 function remains poorly understood. We discovered that K V 2.1 forms micro-clusters, which can transform into large macro-clusters when a critical clustering site (S590) in the channel is phosphorylated in arterial myocytes. Notably, female myocytes exhibit greater phosphorylation of S590, and macro-cluster formation compared to males. Contrary to current models, the activity of K V 2.1 channels seems unrelated to density or macro-clustering in arterial myocytes. Disrupting the K V 2.1 clustering site (K V 2.1 S590A ) eliminated K V 2.1 macro-clustering and sex-specific differences in Ca V 1.2 cluster size and activity. We propose that the degree of K V 2.1 clustering tunes Ca V 1.2 channel function in a sex-specific manner in arterial myocytes. Advanced imaging and electrophysiology show that phosphorylation boosts the size of K V 2.1 clusters, which in turn modulates dihydropyridine-sensitive Ca V 1.2 channel organization and function in arterial smooth muscle, with variations based on sex.