UC Davis

The work contained within this dissertation aims to investigate the role and mechanisms of CaV1.2 and KV2.1 ion channel cluster formation in the membrane of arterial smooth muscle cells. Clustering of ion channels selective for these ions have long been a commonly observed phenotype, yet the mechanisms of cluster formation are still unknown. Overall, this dissertation provides a model by which ion channel clusters form stochastically via a self-assembly process in the membrane based on three mechanistic probabilities: nucleation, growth, and removal. Additionally, we focused on clustering and interactions of two key ion channels, KV2.1 and CaV1.2, in smooth muscle physiology selective for potassium (K+) and calcium (Ca2+) respectively. The opening of these channels play key roles in arterial physiology, counterbalancing each other to affect arterial diameter. The key findings from this work help to elucidate the mechanisms involved in the trafficking of ion channels, maintenance of clusters in the plasma membrane and provide potential reasoning for sex-based differences in smooth muscle physiology. Using a multiscale experimental and computational approach, we describe a key interaction between CaV1.2 and KV2.1 in arterial smooth muscle. This model proposes that KV2.1 clustering state is not a determinate of channel conduction in mesenteric smooth muscle. Additionally, KV2.1 macro-clusters serve as a sex-specific site for increased CaV1.2 clustering and decreasing KV2.1 macro-clustering decreases CaV1.2 channel clustering. This sex-based interaction ultimately plays a key role in Ca2+ dynamics and smooth muscle physiology.