title: Essential role for extracellular Ca(2+) in JNK activation by mechanical stretch in bladder smooth muscle cells.
abstract: Mechanical stretch has been implicated in phenotypic changes as an adaptive response to stretch stress physically loaded in bladder smooth muscle cells (BSMCs). To investigate stretch-induced signaling, we examined the mitogen-activated protein kinase (MAPK) family using rat primary BSMCs. When BSMCs were subjected to sustained mechanical stretch using collagen-coated silicon membranes, activation of c-Jun NH(2)-terminal kinase (JNK) was most relevant among three subsets of MAPK family members: the activity was elevated from 5 min after stretch and peaked at 10 min with an 11-fold increase. Activation of p38 was weak compared with that of JNK, and ERK was not activated at all. JNK activation by mechanical stretch was totally dependent on extracellular Ca(2+) and inhibited by Gd(3+), a blocker of stretch-activated (SA) ion channels. Nifedipine and verapamil, inhibitors for voltage-dependent Ca(2+) channels, had no effect on this JNK activation. Moreover, none of the inhibitors pertussis toxin, genistein, wortmannin, or calphostin C affected stretch-induced JNK activation, indicating that G protein-coupled and tyrosine kinase receptors are unlikely to be involved in this JNK activation. On the other hand, W-7, a calmodulin inhibitor, and cyclosporin A, a calcineurin inhibitor, prevented JNK activation by stretch. These results suggest a novel pathway for stretch-induced activation of JNK in BSMCs: mechanical stretch evokes Ca(2+) influx via Gd(3+)-sensitive SA Ca(2+) channels, resulting in JNK activation under regulation in part by calmodulin and calcineurin.
authors.affiliation: Department of Biomolecular Science, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kushida
authors.forename: Y
authors.initials: Y
authors.lastname: Kabuyama
authors.forename: O
authors.initials: O
authors.lastname: Yamaguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Homma
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012825:Silicon; D013314:Stress, Mechanical; D013449:Sulfonamides / Q000494:pharmacology; D001743:Urinary Bladder / Q000166:cytology / Q000201:enzymology*; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D002118:Calcium; D002147:Calmodulin; D016572:Cyclosporine; D004791:Enzyme Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D012825:Silicon; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides; C017967:W 7