Mechanisms of Vascular Ca_V1.2 Channel Regulation During Diabetic Hyperglycemia

Diabetes is a leading cause of disability and mortality worldwide. A major underlying factor in diabetes is the excessive glucose levels in the bloodstream (e.g., hyperglycemia). Vascular complications directly result from this metabolic abnormality, leading to disabling and life-threatening conditions. Dysfunction of vascular smooth muscle cells is a well-recognized factor mediating vascular complications during diabetic hyperglycemia. The function of vascular smooth muscle cells is exquisitely controlled by different ion channels. Among the ion channels, the L-type Ca_V1.2 channel plays a key role as it is the main Ca²⁺ entry pathway regulating vascular smooth muscle contractile state. The activity of Ca_V1.2 channels in vascular smooth muscle is altered by diabetic hyperglycemia, which may contribute to vascular complications. In this chapter, we summarize the current understanding of the regulation of Ca_V1.2 channels in vascular smooth muscle by different signaling pathways. We place special attention on the regulation of Ca_V1.2 channel activity in vascular smooth muscle by a newly uncovered AKAP5/P2Y₁₁/AC5/PKA/Ca_V1.2 axis that is engaged during diabetic hyperglycemia. We further describe the pathophysiological implications of activation of this axis as it relates to myogenic tone and vascular reactivity and propose that this complex may be targeted for developing therapies to treat diabetic vascular complications.