Tyrosine kinase inhibitors and ATP modulate the conversion of smooth muscle L-type Ca2+ channels toward a second open state.
Properties of smooth and cardiac L-type Ca2+ channels differ prominently in several physiological aspects, including sympathetic modulation. To assess the possible underlying mechanisms, we applied the whole cell patch-clamp technique to guinea pig detrusor smooth muscle cells, in which only L-type Ca2+ channel currents are observed in practice. During depolarization to large positive potentials, the conformation of the majority of L-type Ca2+ channels is converted from the normal (O1) to a second open state (O2), which undergoes little inactivation during depolarization. Extracellular application of genistein, a known tyrosine kinase inhibitor, significantly attenuated the voltage-dependent conversion of Ca2+ channels to O2, accompanied by reduction of availability, whereas genistin, an inactive analog, had little effect. In the absence of ATP in the patch pipette, intracellular application of either genistein or tyrphostin-47 suppressed the conversion to O2. Computer calculation revealed that the acceleration of the O1 to an inactivated state qualitatively reconstructs the unique effects of PTK inhibitors antagonized by ATP. We concluded that under normal conditions smooth muscle L-type Ca2+ channels are already modulated by tyrosine-kinase and ATP-related mechanism(s) and thereby easily achieve the second conversion, which yields voltage-dependent modulation of L-type Ca2+ current analogous to that in cardiac myocytes during beta-adrenoceptor stimulation.
Nakayama
Shinsuke
S
Department of Cell Physiology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. h44673a@nucc.cc.nagoya-u.ac.jp
Ito
Yasushi
Y
Sato
Shinji
S
Kamijo
Atsushi
A
Liu
Hong-Nian
HN
Kajioka
Shunichi
S
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology*; D006168:Guinea Pigs; D008564:Membrane Potentials / Q000502:physiology; D009130:Muscle, Smooth / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D001743:Urinary Bladder / Q000502:physiology
D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D019833:Genistein; D011505:Protein-Tyrosine Kinases