The mitogen-activated protein kinase p38-2 is necessary for the inhibition of N-type calcium current by bradykinin.
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.
Wilk-Blaszczak
M A
MA
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
Stein
B
B
Xu
S
S
Barbosa
M S
MS
Cobb
M H
MH
Belardetti
F
F
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000201:enzymology; D019204:GTP-Binding Proteins / Q000502:physiology; D005910:Glioma; D006822:Hybrid Cells / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009447:Neuroblastoma; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D015220:Calcium Channels; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D011725:Pyridines; D016718:Arachidonic Acid; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; C093642:SB 203580; D001920:Bradykinin; D002118:Calcium