Alpha-Adrenergic Signaling
Explore and order pathway-specific siRNAs, real-time PCR assays, and expression vectors. View pathway information and literature references for your pathway.
  • Click on your proteins of interest in the pathway image or review below
  • Select your genes of interest and click "add selection"
  • When you have finished your gene selection, click "Find Products" to find assays, arrays, or create custom products
Download Image Terms of Use Download PPT
Pathway Navigator
Alpha-Adrenergic Signaling
ADRs (Adrenergic Receptors) 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 (Ref.1). ADRs are members of the super family of cell surface receptors that carry out signaling via GPCR (G-Protein Coupled Receptors) and are divided into nine distinct subtypes: ADR-Alpha1A, ADR-Alpha1B, ADR-Alpha1D, ADR-Alpha2A, ADR-Alpha2B, ADR-Alpha2C, ADR-Beta1, ADR-Beta2 and ADR-Beta3. ADR-Alpha2 is implicated in diverse physiological functions particularly of the cardiovascular system and the CNS (Central Nervous System) (Ref.3 & 4).

Unlike ADR-Beta, which is coupled to activation of AC (Adenyl Cyclase), ADR-Alpha are coupled through G-proteins that activate PLC-Gamma (Phospholipase-C-Gamma). Activation pf PLC-Gamma leads to increased hydrolysis of membrane PIP2 (Phosphatidylinositol-4, 5-Bisphosphate), the products of which are IP3 (Inositol 3-phosphate) and DAG (Diacylglycerol). DAG binds to and activates PKC (Protein Kinase-C) 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 (Calmodulin) and CalmK (Calcium/Calmodulin-Dependent Protein Kinases) resulting in the activation of Glycogen Synthase. Additionally, the Ca2+ ions activate PKC in conjunction with DAG (Ref.6). Hormonal signals (e.g. epinephrine) also trigger the phosphorylation of PHK (Phosphorylase kinase), which takes place through activation of PKA (Protein Kinase-A) in the cAMP (cyclic Adenosine-3’, 5’-Monophosphate) pathway.

The ADR-Alpha1A also utilizes a variety of second messenger pathways to modulate cellular function. In addition to modulating pathways that link the ADR-Alpha1A to calcium movements and smooth muscle contraction, the ADR-Alpha1A is also intimately involved in the regulation of growth promoting responses via the MAP2K (Mitogen-Activated Protein Kinase Kinases) in an Src- and Ras-dependent pathway. ADR-Alpha1A activates all three MAPK pathways, ADR-Alpha1B activates ERK (Extracellular Signal Regulated Kinase) and p38, and ADR-Alpha1D only activates ERK (Ref.6). MAPK, in turn, phosphorylate numerous nuclear transcription factors and other cytosolic proteins making these enzymes key regulators of cellular growth. ADR-Alpha1A-stimulated MAPK signaling pathway potentially contributes to increased DNA synthesis and cell proliferation in human vascular smooth muscle cells (Ref.5).

Because of their widespread distribution in the CNS (Central Nervous System), ADR-Alpha2A 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 (Ref.2). ADR-Alpha2A 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-Alpha1A inhibits lipolysis and is a potential target for the treatment of obesity. Activation of central ADR-Alpha2A causes a powerful antiepileptogenic effect. Two receptor subtypes, ADR-Alpha2A and ADR-Alpha2C, are involved in the hypothermic action of Alpha2-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 Alpha2 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 (Ref.1).