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Tyrosine kinase inhibitors and ATP modulate the conversion of smooth muscle L-type Ca²⁺ channels toward a second open state

Shinsuke Nakayama^*,1, Yasushi Ito, Shinji Sato, Atsushi Kamijo^*, Hong-Nian Liu^* and Shunichi Kajioka^*,2

Department of
^* Cell Physiology and

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

¹Correspondence: Department of Cell Physiology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: h44673a{at}nucc.cc.nagoya-u.ac.jp

ABSTRACT

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 ß-adrenoceptor stimulation.—Nakayama, S., Ito, Y., Sato, S., Kamijo, A., Liu, H.-N., Kajioka, S. Tyrosine kinase inhibitors and ATP modulate the conversion of smooth muscle L-type Ca²⁺ channels toward a second open state.

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