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(Circulation Research. 2008;102:1378.)
© 2008 American Heart Association, Inc.

Cellular Biology

Interaction of ₁-Adrenoceptor Subtypes With Different G Proteins Induces Opposite Effects on Cardiac L-type Ca²⁺ Channel

Jin O-Uchi, Hiroyuki Sasaki, Satoshi Morimoto, Yoichiro Kusakari, Hitomi Shinji, Toru Obata, Kenichi Hongo, Kimiaki Komukai, Satoshi Kurihara

From the Department of Cell Physiology (J.O.-U., S.M., Y.K., S.K.), the Division of Molecular Cell Biology (H.Sasaki, T.O.), the Division of Cardiology (S.M., K.H., K.K.), and the Department of Bacteriology (H.Shinji), The Jikei University School of Medicine, Tokyo, Japan.

Correspondence to Jin O-Uchi, Department of Cell Physiology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461 Japan. E-mail o-uchi{at}jikei.ac.jp

We examined the effect of ₁-adrenoceptor subtype-specific stimulation on L-type Ca²⁺ current (I_Ca) and elucidated the subtype-specific intracellular mechanisms for the regulation of L-type Ca²⁺ channels in isolated rat ventricular myocytes. We confirmed the protein expression of _1A- and _1B-adrenoceptor subtypes at the transverse tubules (T-tubules) and found that simultaneous stimulation of these 2 receptor subtypes by nonsubtype selective agonist, phenylephrine, showed 2 opposite effects on I_Ca (transient decrease followed by sustained increase). However, selective _1A-adrenoceptor stimulation (0.1 µmol/L A61603) only potentiated I_Ca, and selective _1B-adrenoceptor stimulation (10 µmol/L phenylephrine with 2 µ mol/L WB4101) only decreased I_Ca. The positive effect by _1A-adrenoceptor stimulation was blocked by the inhibition of phospholipase C (PLC), protein kinase C (PKC), or Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). The negative effect by _1B-adrenoceptor stimulation disappeared after the treatment of pertussis toxin or by the prepulse depolarization, but was not attriburable to the inhibition of cAMP-dependent pathway. The translocation of PKC and to the T-tubules was observed only after _1A-adrenoceptor stimulation, but not after _1B-adrenoceptor stimulation. Immunoprecipitaion analysis revealed that _1A-adrenoceptor was associated with G_q/11, but _1B-adrenoceptor interacted with one of the pertussis toxin-sensitive G proteins, G_o. These findings demonstrated that the interactions of ₁-adrenoceptor subtypes with different G proteins elicit the formation of separate signaling cascades, which produce the opposite effects on I_Ca. The coupling of _1A-adrenoceptor with G_q/11-PLC-PKC-CaMKII pathway potentiates I_Ca. In contrast, _1B-adrenoceptor interacts with G_o, of which the β-complex might directly inhibit the channel activity at T-tubules.

Key Words: ₁-adrenoceptor • L-type Ca²⁺ channel • G protein • PKC