New insights into the intracellular mechanisms by which PGI2 analogues elicit vascular relaxation: cyclic AMP-independent, Gs-protein mediated-activation of MaxiK channel.

Prostaglandin I2 (PGI2, prostacyclin), an eicosanoid of the cyclooxygenase pathway, causes relaxation of vascular smooth muscle in most blood vessels and inhibits platelet aggregation. PGI2 and its stable analogues activate a specific cell-surface receptor (IP receptor, IPR), which is coupled to adenylyl cyclase through G(s)-protein. Elevation of 3': 5'-cyclic monophosphate (cyclic AMP, cAMP) levels has been considered to be a key cellular event to trigger blood vessel relaxation by IP agonists; however, its exclusive role has been recently challenged. Downstream effectors of the IP agonist metabolic cascade are plasma membrane K+ channels that upon activation would cause smooth muscle cell hyperpolarization and relaxation. The K+ channel candidates include ATP-sensitive K+ (KATP) channel and large conductance, Ca2+ -activated K+ (MaxiK, BK) channel. The contribution of each K+ channel subtype would be governed by their relative expression and/or particular co-localization with different proteins of the IPR signaling cascade in each vascular bed. Scrutiny of the cellular mechanisms underlying IPR-activated vascular relaxation of a large conduit artery revealed that relaxation by an IP agonist, beraprost, is elicited through cAMP-independent pathway as well as by a cAMP-dependent route. Both mechanisms include activation of MaxiK channels. The cAMP-independent vasorelaxant mechanism is partly attributed to a direct activation of MaxiK channel by G(s)-protein. In this review article, we discuss cAMP-dependent and -independent mechanisms by which IPR stimulation activates MaxiK channel. Our recent work demonstrates a functional tight coupling between IPR and MaxiK channel through a cAMP-independent, G(s)-protein mediated mechanism(s) in vascular smooth muscle.