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 Gs-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 cAMPdependent route. Both mechanisms include activation of MaxiK channels. The cAMP-independent vasorelaxant mechanism is partly attributed to a direct activation of MaxiK channel by Gs-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, Gs-protein mediated mechanism(s) in vascular smooth muscle.
Keywords: adenylyl cyclase, beraprost, cyclic monophosphate (cyclic amp, camp), gs-protein, prostaglandin I2 pgi2, prostacyclin), pgi2 receptor (ip receptor, ipr), vascular smooth muscle relaxation
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