Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
Mol Cell. 2024 Oct 17;84(20):3997-4015.e7. doi: 10.1016/j.molcel.2024.09.009. Epub 2024 Oct 3.
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.
三磷酸肌醇（IP）引发的 Ca 信号的空间组织是其多功能性的基础。低刺激强度会引发 Ca 微泡，这是一种局部 Ca 信号，由簇内的几个 IP 受体（IPR）产生，并固定在质膜下。更强的刺激会引发全局 Ca 信号。由于释放的 Ca 会刺激更多的 IPR，Ca 信号会再生性传播。这种潜在的爆炸性机制是如何受到限制以允许局部 Ca 信号的？我们开发了一些方法，可以在 G 蛋白偶联受体（GPCR）激活后拦截并取代 IP 的笼状类似物的光解来产生 IP。我们发现，磷脂酰肌醇 4,5-二磷酸（PIP）通过部分占据其 IP 结合位点来预先激活 IPR，以响应 IP。随着 GPCR 刺激 IP 的形成，它们也会耗尽 PIP，从而解除预刺激。PIP 的损失会重置 IPR 的敏感性并延迟从局部到全局 Ca 信号的转变。通过 GPCR 对 IPR 的 PIP 和 IP 的双重调节控制了从局部到全局 Ca 信号的转变。
