Figure 3. Model for suppression of K_V channel expression and function in diabetes.

PKA-mediated phosphorylation of activation of serine 1928 induces potentiation of LTCCs in response to hyperglycemia and during diabetes (62). This leads to increased global Ca²⁺ influx and contraction. The increase in Ca²⁺ influx promotes activation of the AKAP150-targeted calcineurin, which dephosphorylates NFATc3 and allows its nuclear translocation where the transcription factor can suppress the expression of K_V2.1 (but not K_V1.2 and K_V1.5) subunits. This reduction in K_V2.1 expression and function decreases voltage-gated K⁺ currents and the negative feedback membrane potential hyperpolarization, thus leading to membrane potential depolarization, further Ca²⁺ influx through LTCCs, vascular smooth muscle contraction and enhanced vascular tone. Whether changes in K_V7.X subunits during diabetes proceed through the calcineurin/NFATc3 signaling pathway and similar changes occur in the human vasculature require further investigation. Illustration of the interaction between AKAP150 and LTCC does not necessarily reflect the native interaction between these proteins. The cartoon was drawn as such for simplicity.