Dual regulation of IP receptors by IP and PIP controls the transition from local to global Ca signals.

The spatial organization of inositol 1,4,5-trisphosphate (IP)-evoked Ca signals underlies their versatility. Low stimulus intensities evoke Ca puffs, localized Ca signals arising from a few IP receptors (IPRs) within a cluster tethered beneath the plasma membrane. More intense stimulation evokes global Ca signals. Ca signals propagate regeneratively as the Ca released stimulates more IPRs. How is this potentially explosive mechanism constrained to allow local Ca signaling? We developed methods that allow IP produced after G-protein coupled receptor (GPCR) activation to be intercepted and replaced by flash photolysis of a caged analog of IP. We find that phosphatidylinositol 4,5-bisphosphate (PIP) primes IPRs to respond by partially occupying their IP-binding sites. As GPCRs stimulate IP formation, they also deplete PIP, relieving the priming stimulus. Loss of PIP resets IPR sensitivity and delays the transition from local to global Ca signals. Dual regulation of IPRs by PIP and IP through GPCRs controls the transition from local to global Ca signals.