An essential role of Cav1.2 L-type calcium channel for urinary bladder function.
Mice deficient in the smooth muscle Cav1.2 calcium channel (SMACKO, smooth muscle alpha1c-subunit calcium channel knockout) have a severely reduced micturition and an increased bladder mass. L-type calcium current, protein, and spontaneous contractile activity were absent in the bladder of SMACKO mice. K+ and carbachol (CCh)-induced contractions were reduced to 10-fold in detrusor muscles from SMACKO mice. The dihydropyridine isradipine inhibited K+- and CCh-induced contractions of muscles from CTR but had no effect in muscles from SMACKO mice. CCh-induced contraction was blocked by removing extracellular Ca2+ but was unaffected by the PLC inhibitor U73122 or depletion of intracellular Ca2+ stores by thapsigargin. In muscles from CTR and SMACKO mice, CCh-induced contraction was partially inhibited by the Rho-kinase inhibitor Y27632. These results show that the Cav1.2 Ca2+ channel is essential for normal bladder function. The Rho-kinase and Ca2+-release pathways cannot compensate the lack of the L-type Ca2+ channel.
Wegener
Jörg W
JW
Institut für Pharmakologie und Toxikologie, Technische Universität München, Biedersteiner Str. 29, D-80802 München, Germany. Wegener@ipt.med.tu-muenchen.de
Schulla
Verena
V
Lee
Tae-Seong
TS
Koller
Angela
A
Feil
Susanne
S
Feil
Robert
R
Kleppisch
Thomas
T
Klugbauer
Norbert
N
Moosmang
Sven
S
Welling
Andrea
A
Hofmann
Franz
F
D000577:Amides / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D015640:Ion Channel Gating; D017136:Ion Transport / Q000187:drug effects; D017275:Isradipine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019284:Thapsigargin / Q000494:pharmacology; D001743:Urinary Bladder / Q000502:physiology*; D014555:Urination Disorders / Q000235:genetics / Q000503:physiopathology; D054460:rho-Associated Kinases
D000577:Amides; D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D004963:Estrenes; D047908:Intracellular Signaling Peptides and Proteins; C419385:L-type calcium channel alpha(1C); D011725:Pyridines; D011760:Pyrrolidinones; D011976:Receptors, Muscarinic; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C108830:Y 27632; D019284:Thapsigargin; D002217:Carbachol; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D002118:Calcium; D017275:Isradipine