IP₃-induced interactions between IP₃Rs and ion channels in arterial SMCs. Induction of Ca²⁺ release from the SR via IP₃R (solid orange arrows) is the best-known mechanism of action of IP₃. Non-canonical IP₃ signaling is independent of SR Ca²⁺ release and involves an IP₃-induced interaction of IP₃R1 with plasma membrane channels such as TRPC3 and BK_Ca (red arrowheads), possibly localized in membrane caveolae. TRPC3 activation by IP₃R1 induces a nonselective cation current (I_Cat; solid green arrow) that depolarizes the cell membrane, activating VDCC and BK_Ca channels (dashed green arrows). BK_Ca channels are also activated by Ca²⁺ (dashed orange arrows). Whereas VDCCs mediate Ca²⁺ influx through the plasma membrane (purple arrow) leading to contraction, K⁺ efflux through BK_Ca channels (blue arrow) leads to hyperpolarization of the cell membrane, which closes VDCCs, leading to SMC relaxation.