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Functional Role of Tryptophan Residues in the Fourth Transmembrane Domainof the CB 2 Cannabinoid Receptor
Author(s) -
Rhee ManHee,
Nevo Igal,
Bayewitch Michael L.,
Zagoory Orna,
Vogel Zvi
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0752485.x
Subject(s) - cannabinoid , tryptophan , chemistry , cannabinoid receptor , receptor , neuroscience , transmembrane protein , pharmacology , biochemistry , biology , amino acid , agonist
Several tryptophan (Trp) residues are conserved in Gprotein‐coupled receptors (GPCRs). Relatively little is known about thecontribution of these residues and especially of those in the fourthtransmembrane domain in the function of the CB 2 cannabinoidreceptor. Replacing W158 (very highly conserved in GPCRs) and W172 (conservedin CB 1 and CB 2 cannabinoid receptors but not in manyother GPCRs) of the human CB 2 receptor with A or L or with F or Yproduced different results. We found that the conservative change of W172 to For Y retained cannabinoid binding and downstream signaling (inhibition ofadenylyl cyclase), whereas removal of the aromatic side chain by mutating W172to A or L eliminated agonist binding. W158 was even more sensitive to beingmutated. We found that the conservative W158F mutation retained wild‐typebinding and signaling activities. However, W158Y and W158A mutants completelylost ligand binding capacity. Thus, the Trp side chains at positions 158 and172 seem to have a critical, but different, role in cannabinoid binding to thehuman CB 2 receptor.