Extracellular agonists linked to inositol-1,4,5-trisphosphate (IP) formation elicit cytosolic Ca oscillations in many cell types, but despite a common signaling pathway, distinct agonist-specific Ca 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 Ca oscillations, whereas UTP acting through P2Y2R elicits broad Ca oscillations, with composite patterns observed for ATP. P2XRs do not play a role at physiological agonist levels. The discrete Ca signatures reflect differential effects of protein kinase C (PKC), which selectively modifies the falling phase of the Ca spikes. Negative feedback by PKC limits the duration of P2Y1R-induced Ca spikes in a manner that requires extracellular Ca. By contrast, P2Y2R is resistant to PKC negative feedback. Thus, the PKC leg of the bifurcated IP signaling pathway shapes unique Ca oscillation patterns that allows for distinct cellular responses to different agonists.