Selective coupling of type 6 adenylyl cyclase with type 2 IP3 receptors mediates direct sensitization of IP3 receptors by cAMP

Interactions between cyclic adenosine monophosphate (cAMP) and Ca²⁺ are widespread, and for both intracellular messengers, their spatial organization is important. Parathyroid hormone (PTH) stimulates formation of cAMP and sensitizes inositol 1,4,5-trisphosphate receptors (IP₃R) to IP₃. We show that PTH communicates with IP₃R via “cAMP junctions” that allow local delivery of a supramaximal concentration of cAMP to IP₃R, directly increasing their sensitivity to IP₃. These junctions are robust binary switches that are digitally recruited by increasing concentrations of PTH. Human embryonic kidney cells express several isoforms of adenylyl cyclase (AC) and IP₃R, but IP₃R2 and AC6 are specifically associated, and inhibition of AC6 or IP₃R2 expression by small interfering RNA selectively attenuates potentiation of Ca²⁺ signals by PTH. We define two modes of cAMP signaling: binary, where cAMP passes directly from AC6 to IP₃R2; and analogue, where local gradients of cAMP concentration regulate cAMP effectors more remote from AC. Binary signaling requires localized delivery of cAMP, whereas analogue signaling is more dependent on localized cAMP degradation.