Organization of beta-adrenoceptor signaling compartments by sympathetic innervation of cardiac myocytes.
The sympathetic nervous system regulates cardiac function through the activation of adrenergic receptors (ARs). beta(1) and beta(2)ARs are the primary sympathetic receptors in the heart and play different roles in regulating cardiac contractile function and remodeling in response to injury. In this study, we examine the targeting and trafficking of beta(1) and beta(2)ARs at cardiac sympathetic synapses in vitro. Sympathetic neurons form functional synapses with neonatal cardiac myocytes in culture. The myocyte membrane develops into specialized zones that surround contacting axons and contain accumulations of the scaffold proteins SAP97 and AKAP79/150 but are deficient in caveolin-3. The beta(1)ARs are enriched within these zones, whereas beta(2)ARs are excluded from them after stimulation of neuronal activity. The results indicate that specialized signaling domains are organized in cardiac myocytes at sites of contact with sympathetic neurons and that these domains are likely to play a role in the subtype-specific regulation of cardiac function by beta(1) and beta(2)ARs in vivo.
Shcherbakova
Olga G
OG
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 95305, USA.
Hurt
Carl M
CM
Xiang
Yang
Y
Dell'Acqua
Mark L
ML
Zhang
Qi
Q
Tsien
Richard W
RW
Kobilka
Brian K
BK
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D051244:Caveolin 3 / Q000378:metabolism; D002451:Cell Compartmentation; D002478:Cells, Cultured; D018920:Coculture Techniques; D000074288:Discs Large Homolog 1 Protein; D051528:Guanylate Kinases; D006321:Heart / Q000294:innervation* / Q000502:physiology; D021962:Membrane Microdomains / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D009469:Neuromuscular Junction / Q000378:metabolism / Q000648:ultrastructure; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D017779:Sympathetic Fibers, Postganglionic / Q000378:metabolism* / Q000648:ultrastructure; D013570:Synaptic Membranes / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology*
D054758:A Kinase Anchor Proteins; C487775:AKAP5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D051244:Caveolin 3; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D008565:Membrane Proteins; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D051528:Guanylate Kinases