Receptor-specific Ca²⁺ oscillation patterns mediated by differential regulation of P2Y purinergic receptors in rat hepatocytes

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.