Published online before print May 8, 2008, doi: 10.1161/CIRCRESAHA.107.167734
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Submitted on November 13, 2007
Revised on April 16, 2008
Accepted on April 30, 2008
Interaction of 
1-Adrenoceptor Subtypes With Different G Proteins Induces Opposite Effects on Cardiac L-type Ca2+ Channel
Jin O-Uchi *;
From the Department of Cell Physiology (J.O.-U., S.M., Y.K., S.K.), the Division of Molecular Cell Biology (H.S., T.O.), the Division of Cardiology (S.M., K.H., K.K.), and the Department of Bacteriology (H.S.), The Jikei University School of Medicine, Tokyo, Japan.
* To whom correspondence should be addressed. E-mail: o-uchi{at}jikei.ac.jp.
We examined the effect of 
1-adrenoceptor subtype-specific stimulation on L-type Ca2+ current (ICa) 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 ICa (transient decrease followed by sustained increase). However, selective 1A-adrenoceptor stimulation (
0.1 µmol/L A61603) only potentiated ICa, and selective 1B-adrenoceptor stimulation (10 µmol/L phenylephrine with 2 µ mol/L WB4101) only deceased ICa. 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 Gq/11, but 1B-adrenoceptor interacted with one of the pertussis toxin-sensitive G proteins, Go. 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 ICa. The coupling of 1A-adrenoceptor with Gq/11-PLC-PKC-CaMKII pathway potentiates ICa. In contrast, 1B-adrenoceptor interacts with Go, of which the 
-complex might directly inhibit the channel activityat T-tubules.
Key words:
1-adrenoceptor •
L-type Ca2+ channel •
G protein •
PKC
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