Receptor-specific Ca

Summary Extracellular agonists linked to inositol-1,4,5-trisphosphate (IP3) formation elicit cytosolic Ca2+ oscillations in many cell types, but despite a common signaling pathway, distinct agonist-specific Ca2+ spike patterns are observed. Using qPCR, we show that rat hepatocytes express multiple purinergic P2Y and P2X receptors (R). ADP acting through P2Y1R elicits narrow Ca2+ oscillations, whereas UTP acting through P2Y2R elicits broad Ca2+ oscillations, with composite patterns observed for ATP. P2XRs do not play a role at physiological agonist levels. The discrete Ca2+ signatures reflect differential effects of protein kinase C (PKC), which selectively modifies the falling phase of the Ca2+ spikes. Negative feedback by PKC limits the duration of P2Y1R-induced Ca2+ spikes in a manner that requires extracellular Ca2+. By contrast, P2Y2R is resistant to PKC negative feedback. Thus, the PKC leg of the bifurcated IP3 signaling pathway shapes unique Ca2+ oscillation patterns that allows for distinct cellular responses to different agonists.
Graphical abstract
Highlights • Distinct stereotypic Ca2+ oscillations are elicited by P2Y1 and P2Y2 receptors • P2X receptors do not contribute to the generation of Ca2+ oscillations • Agonist-specific Ca2+ spike shapes reflect discrete modes of PKC negative feedback • Bifurcation of IP3/PKC signaling yields unique Ca2+ oscillation signatures
Biological sciences; Cell biology; Cellular physiology; Functional aspects of cell biology