A Common Molecular Basis for Exogenous and Endogenous Cannabinoid Potentiation of Glycine Receptors

作者：Xiong Wei; Wu Xiongwu; Lovinger David M; Zhang Li^*

来源：Journal of Neuroscience, 2012, 32(15): 5200-5208.

DOI：10.1523/JNEUROSCI.6347-11.2012

Both exogenous and endogenous cannabinoids can allosterically modulate glycine receptors (GlyRs). However, little is known about the molecular basis of cannabinoid-GlyR interactions. 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 alpha 1, rat alpha 2 and alpha 3 GlyRs. While the alpha 1 and alpha 3 subunits were highly sensitive to AEA-induced potentiation, the alpha 2 subunit was relatively insensitive to AEA. Switching a serine at 296 and 307 in the TM3 (transmembrane domain 3) of the alpha 1 and alpha 3 subunits with an alanine (A) at the equivalent position in the alpha 2 subunit converted the alpha 1/alpha 3 AEA-sensitive receptors to sensitivity resembling that of alpha 2. The S296 residue is also critical for exogenous cannabinoid-induced potentiation of I-Gly. 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 I-Gly, desoxy-AEA inhibited potentiation produced by both Delta(9)-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 I-Gly when applied alone but inhibited the potentiation of I-Gly 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 alpha 1 and alpha 3 subunits.

• 出版日期2012-4-11