Figure 2.

Proposed model for the regulation of vascular smooth muscle cell (VSMC) excitability by macromolecular complexes. The magnitude of Ca²⁺ influx via Ca_V1.2 is critical for the control of excitation-contraction and excitation-transcription coupling in these cells. Under physiological conditions, K⁺ channels oppose pressure-induced depolarization to limit Ca_V1.2 activity and VSMC contractility. The activity of K⁺ and Ca_V1.2 channels can be regulated by cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and the protein phosphatase PP2B, which are targeted to the specific channels and G protein-coupled receptors (GPCRs) by AKAP5 and/or PSD-95, and their function may be altered during pathological conditions. Both PKA and PKC can phosphorylate Ca_V1.2 on S1928 (dashed blue lines) but are regulated by different GPCRs. PKA can also regulate K⁺ channels of the K_V1 family. In turn, K_V1 channels negatively control Ca_V1.2 activity. Whether the hypothesized interactions (solid red lines), including those involving the GPCRs that mediate angiotensin II (angII) and high glucose (HG) signaling, PSD-95, and AKAP5, occur in native VSMCs is unclear.