Fig. 3. Signaling pathways involved in regulation and modulation of the smooth muscle K_ATP channel.

The K_ATP channel determines, in part, the membrane potential of the smooth muscle cell and, hence, the contractile state. Vasoactive factors that inhibit K_ATP activity cause membrane depolarization, activation of voltage-dependent Ca²⁺-channels (VDCC), a rise in intracellular [Ca²⁺] and smooth muscle contraction. Conversely, factors that activate K_ATP prevent the depolarization-dependent rise in [Ca²⁺] and promote smooth muscle dilation. (A) Endogenous vasodilators, including epinephrine, adenosine, prostacyclin (PGl₂), calcitonin-generated peptide (CGRP), and the vasoactive intestinal peptide (VIP), stimulate K_ATP activity through the classic G-protein (Gs)/adenylate cyclase (AC)/protein kinase A (PKA) signaling pathway. Serine/threonine phosphorylation at several key residue in SUR2B (Thr633, Ser1387, and Ser1465) is thought to underlie channel activation. Conversely, nitric oxide activates K_ATP through the protein kinase G (PKG) signaling pathway. Hypoxia and metabolic poisons (dinitrophenol and deoxygluxose) indirectly activate K_ATP by suppressing oxidative phosphorylation, resulting in a decrease in the ATP/ADP levels. The K+-channel opener drugs (KCOs) (eg. pinacidil and diazoxide) promote their anti-hypertensive effects by opening vascular smooth K_ATP channels via interaction with the SUR2B subunit. (B) Vasoconstrictor agonists that target VSM K_ATP to promote contraction include the neurotransmitter serotonin (5-HT), angiotensin-II, endothelin-I, and the pro-inflammatory histamine. Binding of vasoconstrictors to the G-protein receptor subtypes, Gi or Gq, indirectly activates the PKC-ε isoform. In turn, PKCε-mediated phosphorylation of a serine-rich motif in the C-terminus of Kir6.1 results in a decrease in the frequency of channel openings. Ca²⁺-activated calcineurin (phosphatase type 2B) inhibits VSM K_ATP although the mechanism is unclear. Sulfonylurea compounds (e.g glibenclamide) induce vasoconstriction by binding to the SUR2B subunit causing K_ATP channel closure.