Tyrosine kinases indirectly raise intracellular calcium concentration ([Ca²⁺]_i) by activating phospholipases that generate inositol 1,4,5-trisphosphate (IP₃). IP₃ activates the IP₃ receptor (IP₃R), an intracellular calcium release channel on the endoplasmic reticulum. T cell receptor stimulation triggered a physical association between the nonreceptor protein tyrosine kinase Fyn and the IP₃R, which induced tyrosine phosphorylation of the IP₃R. Fyn activated an IP₃-gated calcium channel in vitro, and tyrosine phosphorylation of the IP₃R during T cell activation was reduced in thymocytes from fyn^−/− mice. Thus, activation of the IP₃R by tyrosine phosphorylation may play a role in regulating [Ca²⁺]_i.