Schematic depiction of the signaling pathways using PIP₂ signals suggested in this study. The signals provoked by M₁ mACh (left) or bradykinin B₂ (right) receptors are shown. I_Ca from N-type calcium channels is shown inhibited by muscarinic stimulation (left) but not normally inhibited by bradykinin (right). Both receptor types activate PLC via G_q/11, resulting in hydrolysis of PIP₂. In the hypothesis of Delmas et al. (2004), clustering of B₂ but not M₁ receptors in the plasma membrane together with IP₃ receptors in the endoplasmic reticulum (ER) causes the former, but not the latter, to release [Ca²⁺]_i downstream of IP₃ production. We suggest that the bradykinin-induced [Ca²⁺]_i signals induce PIP₂ synthesis, concurrent with its hydrolysis, via stimulation of PI4-kinase (PI4-K) by NCS-1, which acts as the sensor for increases in [Ca²⁺]_i. Thus, bradykinin does not normally inhibit the N-type Ca²⁺ channel as a result of compensatory PIP₂ synthesis, but muscarinic agonists do so robustly from consumption of PIP₂.