Beta-Adrenergic Signaling
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Beta-Adrenergic Signaling
The rate and strength of beating of the heart is under the reciprocal control of the Adrenergic (sympathetic) and Cholinergic (parasympathetic) systems. Increased strength (inotropy) in cardiac beating in response to hormones like the blood-borne Epinephrine or to neurally delivered Norepinephrine is mediated by ADR-Beta (Beta-Adrenergic Receptors) (Ref.1), which are members of the superfamily of cell surface receptors that carry out signaling via coupling to G-Proteins (Guanine nucleotide binding proteins). ADR forms the interface between the endogenous Catecholamines, Adrenaline, Epinephrine and Norepinephrine and a wide array of target cells in the body to mediate the biological effects of the Sympathetic Nervous System. They serve critical roles in maintaining homeostasis in normal physiologic settings as well as pathologic states. The family of human ADRs consists of nine subtypes: ADR-Alpha1A, ADR-Alpha1B, ADR-Alpha1D, ADR-Alpha2A, ADR-Alpha2B, ADR-Alpha2C, ADR-Beta1, ADR-Beta2, and ADR-Beta3. Although several of these receptors can couple to more than one G-Protein , the classic coupling pathways for ADR-Alpha1A, ADR-Alpha2A, and ADR-Beta are via G-AlphaQ (stimulation of PLC, Phopholipase-C), G-AlphaI (inhibition of AC, Adenylyl Cyclase), and G-AlphaS (stimulation of AC), respectively (Ref.2 & 5). Stimulation of ADR-Beta is broadly involved in metabolic regulation, growth control, muscle contraction, cell survival, and cell death. In the heart, ADR-Beta stimulation by Catecholamines serves as the most powerful regulatory mechanism to enhance myocardial performance in response to stress or exercise by activating the classic stimulatory pathway comprising the G-Proteins (Ref.4).

As the prototypical GPCR (G-Protein Coupled Receptors), ADR-Beta interacts exclusively with G-AlphaS, which in turn activates AC and cAMP (cyclic Adenosine Monophosphate) formation. Subsequently, activation of cAMP-dependent PKA (Protein Kinase-A) leads to phosphorylation of a set of regulatory proteins involved in cardiac excitation-contraction coupling and energy metabolism, including L-Type Ca2+ Channels, the SERCA (Sarco- and Endoplasmic Reticulum Ca2+ ATPase), membrane protein Phospholamban, the myofibrillar protein Troponin-I, and Glycogen Phosphorylase Kinase (Ref.5). Regulation of SERCA depends on the phosphorylation state of Phospholamban. When Phospholamban is phosphorylated, its inhibitory effect towards SERCA is relieved, leading to an enhanced myocardial performance. The ADR-Beta1 subtype stimulates solely the G-AlphaS pathway, whereas ADR-Beta2 conducts a duet of signaling that includes both G-AlphaS and G-AlphaI. Adenosine can also stimulate G-AlphaI activity via activation of AdoRA1 (Adenosine A1 Receptor). Stimulation of ADR-Beta1 activates two pathways mediated by CalmKII (Calmodulin (Calm)-dependent Kinase-II) and PKA. The two pathways are called upon in tandem to fulfill distinctly different functional roles. Acute ADR-Beta1 stimulation rapidly activates the cAMP/PKA pathway, whereas prolonged ADR-Beta1 stimulation causes desensitization of cAMP/PKA signaling. This fast cAMP/PKA response is crucial to sympathetic control over the heart rate and myocardial contraction, allowing the heart to increase its output within seconds in response to a “fight-or-flight” situation (Ref.4).

In the heart, dual coupling of the ADR-Beta2 to G-AlphaS and G-AlphaI results in compartmentalization of the G-AlphaS-stimulated cAMP signal, thus selectively affecting plasma membrane effectors (such as L-Type Ca2+ Channels) and bypassing cytoplasmic target proteins (Phospholamban and Troponin-I). The ADR-Beta2-to-G-AlphaI branch delivers a powerful cell survival signal that counters apoptosis induced by the concurrent G-AlphaS-mediated signal or by a wide range of assaulting factors. This survival pathway sequentially involves G-AlphaI, G-Beta, G-Gamma , PI3K (Phosphoinositide-3 Kinase), and Akt/PKB (Protein Kinase-B). G-Beta and G-Gamma released from the G-AlphaI-coupled ADR-Beta activates MAP2K (Mitogen-Activated Protein Kinase Kinases) in a Src-SOS and Ras-dependent pathway. Mixed ADR-Beta stimulation increases cardiac contractility (positive inotropic effect), accelerate cardiac relaxation (positive lusitropic effect), and increase heart rate (positive chronotropic effect) (Ref.6). ADR-Beta1-generated cAMP signaling can broadcast throughout the cell, whereas ADR-Beta2-initiated cAMP signaling is confined to subsarcolemmal microdomains. Hormones that elevate intracellular cAMP also increase PPtase activity. PPtase activation may affect cPLA2 (Cytosolic Phospholipase-A2), which catalyzes the release of Arachidonic Acid from membrane phospholipids. Arachidonic acid in turn serves as precursor for a wide spectrum of biologic effectors that are involved in inflammatory responses and other cellular processes.

ADR-Beta signaling is an important regulator of myocardial function. During the progression of heart failure, a reproducible series of biochemical events occur that affects ADR-Beta signaling and cardiac function. The ADR-Beta1 is the predominant ADR-Beta in heart whereas the ADR-Beta2 predominates in liver, lung, and smooth muscle (Ref.1). Over expression of ADR-Beta2 in the myocardium improves cardiac function and therefore it is being developed as a potential therapy for CHF (Congestive Heart Failure). Stimulation of ADR-Beta can both enhance conduction in normal ventricular myocardium and also induce arrhythmic events in a number of cardiac disease states (Ref.6). Prolonged ADR-Beta signaling stimulates cardiac myocyte apoptosis, which is implicated in cardiac ischemic and reperfusion injury and is involved in the transition from cardiac hypertrophy to decompensated heart failure. Selective agonists for the ADR-Beta2 also play an important role in asthma therapy, whereas ADR-Beta1 antagonists are first-line medication for patients with hypertension, coronary heart disease, or chronic heart failure (Ref.3). Selective enhancement of ADR-Beta2 signaling may provide a therapeutic strategy for the prevention and treatment of chronic heart failure because of its evident antiapoptotic and positive inotropic effects (Ref.5).