Assembly of a Ca2+-dependent BK channel signaling complex by binding to beta2 adrenergic receptor.
Large-conductance voltage and Ca2+-activated potassium channels (BKCa) play a critical role in modulating contractile tone of smooth muscle, and neuronal processes. In most mammalian tissues, activation of beta-adrenergic receptors and protein kinase A (PKAc) increases BKCa channel activity, contributing to sympathetic nervous system/hormonal regulation of membrane excitability. Here we report the requirement of an association of the beta2-adrenergic receptor (beta2AR) with the pore forming alpha subunit of BKCa and an A-kinase-anchoring protein (AKAP79/150) for beta2 agonist regulation. beta2AR can simultaneously interact with both BKCa and L-type Ca2+ channels (Cav1.2) in vivo, which enables the assembly of a unique, highly localized signal transduction complex to mediate Ca2+- and phosphorylation-dependent modulation of BKCa current. Our findings reveal a novel function for G protein-coupled receptors as a scaffold to couple two families of ion channels into a physical and functional signaling complex to modulate beta-adrenergic regulation of membrane excitability.
Liu
Guoxia
G
Division of Cardiology and Center for Molecular Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Shi
Jingyi
J
Yang
Lin
L
Cao
Luxiang
L
Park
Soo Mi
SM
Cui
Jianmin
J
Marx
Steven O
SO
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D019281:Dimerization; D004594:Electrophysiology; D005260:Female; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D008168:Lung / Q000378:metabolism; D008954:Models, Biological; D009130:Muscle, Smooth / Q000378:metabolism; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D001743:Urinary Bladder / Q000378:metabolism; D014981:Xenopus
C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D002118:Calcium