Dual regulation of IP3 receptors by IP3 and PIP2 controls the transition from local to global Ca2+ signals
Adelina Ivanova, Peace Atakpa‐Adaji, Shanlin Rao, Maria Martí-Solano, Colin W. Taylor
Abstract
The spatial organization of inositol 1,4,5-trisphosphate (IP 3 )-evoked Ca 2+ signals underlies their versatility. Low stimulus intensities evoke Ca 2+ puffs, localized Ca 2+ signals arising from a few IP 3 receptors (IP 3 Rs) within a cluster tethered beneath the plasma membrane . More intense stimulation evokes global Ca 2+ signals. Ca 2+ signals propagate regeneratively as the Ca 2+ released stimulates more IP 3 Rs. How is this potentially explosive mechanism constrained to allow local Ca 2+ signaling? We developed methods that allow IP 3 produced after G-protein coupled receptor (GPCR) activation to be intercepted and replaced by flash photolysis of a caged analog of IP 3 . We find that phosphatidylinositol 4,5-bisphosphate (PIP 2 ) primes IP 3 Rs to respond by partially occupying their IP 3 -binding sites. As GPCRs stimulate IP 3 formation, they also deplete PIP 2 , relieving the priming stimulus. Loss of PIP 2 resets IP 3 R sensitivity and delays the transition from local to global Ca 2+ signals. Dual regulation of IP 3 Rs by PIP 2 and IP 3 through GPCRs controls the transition from local to global Ca 2+ signals.