naling pathway. Of the three beta receptors, beta1 and beta2 are the better understood systems.The highest levels of beta1 are found in the heart and brain; beta2 is expressed in the heart, lung and other tissues. Beta2, due to its role in smooth muscle relaxation, has been the target for the development of short- and long-acting agonists used in the treatment of asthma. Both receptors are important for the stimulation of cardiac performance. Acute activation of the receptors following ventricular dysfunction, while initially beneficial, can lead to heart failure if it becomes chronic. Upon agonist binding, conformational changes lead to binding of the receptor to the GDP-bound G protein complex. Activated receptors act as GEFs to catalyze the release of GDP from the G alpha subunit followed by formation of a stable receptor-G protein complex. GTP binding to the alpha subunit triggers conformational re-arrangements leading to the dissociation of the GTP-bound G alpha from both the beta/gamma and receptor complexes and association with downstream effectors. For Gs alpha, the  effectors are members of the adenylyl cyclase family that catalyze the conversion of ATP to cAMP.  G alpha has intrinsic but slow GTPase activity; members of the RGS family act as GAPs to promote GTP hydrolysis, termination of the G-protein signal, and re-formation of the GDP-bound and inactive heterotrimer now ready for another possible cycle of activation. PKA signaling exerts a plethora of effects; among its targets in cardiac myocytes are proteins involved in excitation-contraction coupling.  PKA phosphorylates the activated, ligand-bound beta1 and 2 receptors, also targets for phosphorylation by members of the GRK family. Subsequent interaction with beta-arrestin sterically precludes the coupling between the receptor and the G protein, an event referred to as receptor desensitization. Receptor  desensitization is a hallmark of heart failure but its exact role in the condition is still to be determined. Beta-blockers, which compete with catecholamine binding to counteract excessive signaling and by the same token allow the system to 're-sensitize', are the main therapeutics used for treatment. Beta-arrestin is also involved in receptor internalization to clathrin-coated pits followed by clathrin-mediated endocytosis and receptor degradation (downregulation) or recycling, as needed. In addition, beta-arrestins also act as scaffolds to trigger G protein independent signaling pathways downstream of beta adrenergic and other GPCR receptors, primarily MAPK cascades. Of note is that in addition to common targets, the two receptors interact with distinct sets of proteins (not shown). To see the ontology report for annotations, GViewer and download, click here

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