In non‐excitable cells, receptor‐activated Ca 2+ signalling comprises initial transient responses followed by a Ca 2+ entry‐dependent sustained and/or oscillatory phase. Here, we describe the molecular mechanism underlying the second phase linked to signal amplification. An in vivo inositol 1, 4, 5‐trisphosphate (IP 3) sensor revealed that in B lymphocytes, receptor‐activated and store‐operated Ca 2+ entry greatly enhanced IP 3 production, which terminated in phospholipase Cγ2 (PLCγ2)‐deficient cells. Association between receptor‐activated TRPC3 Ca 2+ channels and PLCγ2, which cooperate in potentiating Ca 2+ responses, was demonstrated by co‐immunoprecipitation. PLCγ2‐deficient cells displayed diminished Ca 2+ entry‐induced Ca 2+ responses. However, this defect was canceled by suppressing IP 3‐induced Ca 2+ release, implying that IP 3 and IP 3 receptors mediate the second Ca 2+ phase. Furthermore, confocal visualization of PLCγ2 mutants demonstrated that Ca 2+ entry evoked a C2 domain‐mediated PLCγ2 translocation towards the plasma membrane in a lipase‐independent manner to activate PLCγ2. Strikingly, Ca 2+ entry‐activated PLCγ2 maintained Ca 2+ oscillation and extracellular signal‐regulated kinase activation downstream of protein kinase C. We suggest that coupling of Ca 2+ entry with PLCγ2 translocation and activation controls the amplification and co‐ordination of receptor signalling.