Calcium influx via voltage-dependent calcium channels (ICa,V) links depolarization of excitable cells to critical cellular processes, such as secretion, contraction, and gene transcription. Fast regulation of ICa,V (<1 sec) by G-protein-coupled receptors is a relatively well-defined mechanism, whereas slow (30-60 sec) actions of transmitters and hormones on the same current remain poorly understood. In NG108-15 cells, the kinetically slow inhibition of N-type ICa,V by bradykinin (BK) requires the sequential activation of two G-proteins, heterotrimeric G13 and monomeric Rac1/Cdc42. We have now defined a role in this pathway for the relatively fast-acting p38 mitogen-activated protein kinase (MAPK). The slow inhibition of ICa,V by BK was suppressed specifically by SB203580, a compound that inhibits the p38 family of MAPKs. BK potently and selectively activated a newly discovered p38 family member, p38-2. These data provide the first evidence that a MAPK is involved in the regulation of ICa,V by a receptor-mediated process.