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Functional Selectivity at Receptors for Cannabinoids and Other Lipids

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Functional Selectivity of G Protein-Coupled Receptor Ligands

Part of the book series: The Receptors ((REC))

Abstract

CB1 and CB2 cannabinoid receptors are associated with Gi/o proteins to activate signal transduction pathways that include inhibition of adenylyl cyclase, activation of mitogen activated protein kinase (MAPK), and regulation of ion channels (CB1 only). Agonists for these receptors include structurally diverse cannabinoid, aminoalkylindole, and eicosanoid ligands. Arylpyrazole ligands generally behave as competitive antagonists and inverse agonists to block constitutive activity of the cannabinoid receptors. Allosteric regulators of the CB1 receptor have been identified. One mechanism for functional selectivity of these ligands to direct signal transduction is the ability of certain ligands to behave as agonists for some Gαi subtypes and as inverse agonists for other Gαi subtypes. Biochemical and modeling studies suggest that selectivity can be attributed to conformational changes initiated by interactions within the 7-transmembrane helical bundle that ultimately modulate either the juxtamembrane C-terminal domain to activate Gαi3 or Gαo, and intracellular loop 3 domains to activate Gαi1, Gαi2, or Gαs. Additional selectivity in signaling pathways is conferred by accessory proteins including CRIP1a, FAN, β-arrestin, and GASP1. Close physical association of the CB1 receptor with other pharmacologically distinct GPCRs, including D2 dopamine, opioid, orexin 1, and GABAB receptors, allows ligands acting on one partner to alter the efficacy of ligands for the partner receptors. These mechanisms of ligand-directed functional selectivity can be utilized in the design of pharmacological agents that initiate signal transduction pathways of therapeutic relevance.

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  1. Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC, 27101

    Allyn C. Howlett

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    Kim A. Neve

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Howlett, A.C. (2009). Functional Selectivity at Receptors for Cannabinoids and Other Lipids. In: Neve, K.A. (eds) Functional Selectivity of G Protein-Coupled Receptor Ligands. The Receptors. Humana Press. https://doi.org/10.1007/978-1-60327-335-0_11

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