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Cannabinoid Agonist and Inverse Agonist Regulation of G Protein Coupling

Cannabinoid Agonist and Inverse Agonist Regulation of G Protein Coupling

  1. ThirdEyeFloond
    The Cannabinoid Receptors p173-202

    Cannabinoid Agonist and Inverse Agonist Regulation of G Protein Coupling

    Allyn C. Howlett2 , Lea W. Padgett and Joong-Youn Shim

    Abstract
    The CB1 cannabinoid receptor is a G-protein-coupled receptor (GPCR) that can be stimulated by cannabinoid and nonclassical cannabinoids, aminoalkylindoles, and endocannabinoids. Constitutive activity of CB1 receptors allows inverse agonists such as arylpyrazoles to modulate activity in the absence of an agonist, and can allow sequestration of Gi/o proteins to alter signal transduction involving other receptors. Agonist-stimulated activity can be noncompetitively blocked by allosteric drugs. Agonists selectively activate G proteins, and may behave as inverse agonists for certain subtypes. CB1 receptors can couple to Gs under conditions of inactivation of Gi proteins or unique states of interaction with dopaminergic receptors that might include heterodimerization.
    Structure of the intracellular domains of the CB1 receptor defines the G protein selectivity and activation. Palmitoylation defines the intracellular loop 4 (IL4), and phosphorylation sites can regulate G protein coupling. The CB1 receptor IL3 is relatively long, forming an amphipathic α-helix believed to interact with G proteins. The IL4 can form an α-helical segment at the end of transmembrane (TM) 7, which in a negatively charged environment can exist as a 310-helix. The IL3 interacts with Gi1 and Gi2, whereas the IL4 interacts with Gi3 and Go. Special motifs including YXXIXXL/A, BBXB, or BBXXB, and the IL4 NPXXY(X)5,6F are important for activity. Activation of the CB1 receptor probably involves sequential microconformational changes that may be initiated by a steric trigger as the agonist releases internal-binding energy within its binding pocket.
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