α-Adrenergic Signaling

Adrenergic receptors (ADRs) are expressed on virtually every cell type in the body and are the receptors for Adrenaline, Epinephrine and Norepinephrine within the Sympathetic Nervous System. They serve critical roles in maintaining homeostasis in normal physiologic settings as well as pathologic states. These receptors are also targets for therapeutically administered agonists and antagonists. ADRs carry out signaling via GPCR (G-Protein Coupled Receptors) and are divided into nine distinct subtypes: ADR-α1A, ADR-α1B, ADR-α1D, ADR-α2A, ADR-α2B, ADR-α2C, ADR-β1, ADR-β2 and ADR-β3. ADR-α2 is implicated in diverse physiological functions particularly of the cardiovascular system and the Central Nervous System.Unlike ADR-β, which is coupled to activation of Adenyl Cyclase, ADR-α are coupled through G-proteins that activate PLC-γ. Activation pf PLC-γ leads to increased hydrolysis of membrane PIP2, the products ofwhich are IP3 and DAG. DAG binds to and activates PKC that phosphorylates numerous substrates, one of which is Glycogen Synthase. IP3 binds to IP3R (IP3 Receptors) on the surface of the ER (Endoplasmic Reticulum) leading to release of Ca2+ ions. The Ca2+ ions then interact with Calm and CalmK resulting in the activation of Glycogen Synthase. Additionally, the Ca2+ ions activate PKC in conjunction with DAG. Hormonal signals (e.g. epinephrine) also trigger the phosphorylation of PHK, which takes place through activation of PKA in the cAMP pathway.The ADR-α1A also utilizes a variety of second messenger pathways to modulate cellular function. In addition to modulating pathways that link the ADR-α1A to calcium movements and smooth muscle contraction, the ADR-α1A is also intimately involved in the regulation of growth promoting responses via the MAP2K in a Src- and Ras-dependent pathway. ADR-α1A activates all three MAPK pathways, ADR-α1B activates ERK and p38, and ADR-α1D only activates ERK. MAPK, in turn, phosphorylate numerous nuclear transcription factors and other cytosolic proteins making these enzymes key regulators of cellular growth. ADRα1A stimulated MAPK signaling pathway potentially contributes to increased DNA synthesis and cell proliferation in human vascular smooth muscle cells.Because of their widespread distribution in the Central Nervous System, ADR-α2A not only inhibit release of their own neurotransmitters (autoreceptors) but can also regulate the exocytosis of a number of other neurotransmitters in the central and peripheral nervous system. ADR-α2A mediates part of the diverse biological effects of the endogenous catecholamines Epinephrine and Norepinephrine. They are involved in the control of blood pressure and regulation of body temperature as well as seizure threshold. In adipose tissue, ADR-α1A inhibits lipolysis and is a potential target for the treatment of obesity. Activation of central ADR-α2A causes a powerful antiepileptogenic effect. Two receptor subtypes, ADR-α2A and ADR-α2C, are involved in the hypothermic action of α2-agonists, which are potent analgesics. They can potentiate the analgesic effect of opioids and are used in the postoperative phase or in intensive care as sedative, hypnotic, and analgesic agents. The α2 agonists like clonidine, isoproterenol, medetomidine, and brimonidine are being used to treat patients with hypertension, glaucoma, tumor pain, postoperative pain, and shivering or to block the symptoms of sympathetic over activity during drug withdrawal.