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Here we report that sustained incubation with the endocannabinoid anandamide (AEA) substantially increased the amplitude of glycine-activated current in both rat cultured spinal neurons and in HEK-293 cells expressing human \u03b11, rat \u03b12 and \u03b13 GlyRs. While the \u03b11 and \u03b13 subunits were highly sensitive to AEA-induced potentiation, the \u03b12 subunit was relatively insensitive to AEA. Switching a serine at 296 and 307 in the TM3 (transmembrane domain 3) of the \u03b11 and \u03b13 subunits with an alanine (A) at the equivalent position in the \u03b12 subunit converted the \u03b11\/\u03b13 AEA-sensitive receptors to sensitivity resembling that of \u03b12. The S296 residue is also critical for exogenous cannabinoid-induced potentiation of<jats:italic>I<\/jats:italic><jats:sub>Gly<\/jats:sub>. The magnitude of AEA potentiation decreased with removal of either the hydroxyl or oxygen groups on AEA. While desoxy-AEA was significantly less efficacious in potentiating<jats:italic>I<\/jats:italic><jats:sub>Gly<\/jats:sub>, desoxy-AEA inhibited potentiation produced by both \u0394<jats:sup>9<\/jats:sup>-tetrahydrocannabinol (THC), a major psychoactive component of marijuana, and AEA. Similarly, didesoxy-THC, a modified THC with removal of both hydroxyl\/oxygen groups, did not affect<jats:italic>I<\/jats:italic><jats:sub>Gly<\/jats:sub>when applied alone but inhibited the potentiation of<jats:italic>I<\/jats:italic><jats:sub>Gly<\/jats:sub>induced by AEA and THC. These findings suggest that exogenous and endogenous cannabinoids potentiate GlyRs via a hydrogen bonding-like interaction. Such a specific interaction likely stems from a common molecular basis involving the S296 residue in the TM3 of the \u03b11 and \u03b13 subunits.<\/jats:p>","DOI":"10.1523\/jneurosci.6347-11.2012","type":"journal-article","created":{"date-parts":[[2012,4,11]],"date-time":"2012-04-11T16:29:13Z","timestamp":1334161753000},"page":"5200-5208","source":"Crossref","is-referenced-by-count":59,"title":["A Common Molecular Basis for Exogenous and Endogenous Cannabinoid Potentiation of Glycine Receptors"],"prefix":"10.1523","volume":"32","author":[{"given":"Wei","family":"Xiong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongwu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David 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