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The Mitogen-Activated Protein Kinase p38-2 Is Necessary for the Inhibition of N-Type Calcium Current by Bradykinin

By Malgorzata A. Wilk-blaszczak, Bernd Stein, Shuichan Xu, Miguel S. Barbosa, Melanie H. Cobb and Francesco Belardetti


Calcium influx via voltage-dependent calcium channels (I Ca,V) links depolarization of excitable cells to critical cellular processes, such as secretion, contraction, and gene transcription. Fast regulation of I Ca,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 I Ca,V by bradykinin (BK) requires the sequential activation of two G-proteins, heterotrimeric G 13 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 I Ca,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 I Ca,V by a receptor-mediated process. Key words: G-protein; calcium channels; bradykinin; p38; MAPK; neuroblastoma x glioma; NG108-15; G 13 Depolarization of the neuronal membrane leads to the opening of voltage-activated calcium channels (ICa,V), followed by a rapid increase of the intracellular calcium concentration (Tsien et al., 1991). In turn, the cytoplasmic calcium signal controls a multitude of cellular functions (Kandel et al., 1991). This process is tightly regulated by a variety of hormones and neurotransmitters, in most cases acting on the calcium channels via receptors coupled to heterotrimeric G-proteins (Hepler and Gilman, 1992; Hille

Year: 2013
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