β2 adrenergic receptor complexes with Ca channels and AMPA receptors mediate localized cAMP signaling

Published on February 28, 2011 Updated on August 30, 2018   43 min

Other Talks in the Series: Ion Channels

0:00
Hello. My name is Johannes Hell. I am Professor and Vice Chair for Academic Development in the Department of Pharmacology at the University of California in Davis. I'm also the departmental mentoring director and the director of the NIH-funded pre-doctoral training program in pharmacology. People in my lab are interested in the special temporal analysis of signaling at the postsynaptic site of glutamatergic synapses. Although we are focused on the synapse, our work on the, as it turns out highly localized signaling by cyclic AMP, reaches far beyond the nervous system.
0:44
A number of G-protein coupled receptors act by stimulating cyclic AMP production. Cyclic AMP is in general a diffusible second messenger, yet stimulation of the different receptors in a given cell can lead to different responses. So, general question that I will address today, is how signaling through cyclic AMP can result in defined responses that vary between different G-protein coupled receptors within the same cell. A prominent example are the beta-1 and beta-2 adrenergic receptors in cardiomyocytes. Stimulation of the beta-1 adrenergic receptor leads to PKA mediated phosphorylation of proteins throughout the cardiomyocyte, whereas stimulation of the beta-2 adrenergic receptor, leads to highly localized regulation of proteins within the immediate neighborhood of the L-type calcium channel Cav1.2 which triggers cardiac contraction. A long-standing hypothesis is that the formation of macromolecular signaling complexes that contain all components of the G-protein coupled receptor, GS, adenylyl cyclase, cyclic AMP, PKA cascade, allow spatially restricted cyclic AMP action. However, neither localized signaling by cyclic AMP nor the existence of such signaling complexes had been demonstrated until about 20 years ago. I will discuss our groundbreaking work to identify two different signaling complexes between the beta-2 adrenergic receptor and its key downstream targets, the L-type calcium channel, Cav1.2, and the AMPA-type glutamate receptor.
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β2 adrenergic receptor complexes with Ca channels and AMPA receptors mediate localized cAMP signaling

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