Differential signalling in human cannabinoid CB1 receptors and their splice variants in autaptic hippocampal neurones

作者：Straiker Alex^*; Wager Miller Jim; Hutchens Jacqueline; Mackie Ken

来源：British Journal of Pharmacology, 2012, 165(8): 2660-2671.

DOI：10.1111/j.1476-5381.2011.01744.x

• hCB1
• rCB1
• CB1a
• CB1b
• splice variant
• cannabinoid
• marijuana
• THC

BACKGROUND AND PURPOSE
Cannabinoids such as Delta(9)-tetrahydrocannabinol, the major psychoactive component of marijuana and hashish, primarily act via cannabinoid CB1 and CB2 receptors to produce characteristic behavioural effects in humans. Due to the tractability of rodent models for electrophysiological and behavioural studies, most of the studies of cannabinoid receptor action have used rodent cannabinoid receptors. While CB1 receptors are relatively well-conserved among mammals, human CB1 (hCB(1)) differs from rCB(1) and mCB(1) receptors at 13 residues, which may result in differential signalling. In addition, two hCB(1) splice variants (hCB(1a) and hCB(1b)) have been reported, diverging in their amino-termini relative to hCB(1) receptors. In this study, we have examined hCB(1) signalling in neurones.
EXPERIMENTAL APPROACH hCB(1), hCB(1a) hCB(1b) or rCB(1) receptors were expressed in autaptic cultured hippocampal neurones from CB1-/- mice. Such cells express a complete endogenous cannabinoid signalling system. Electrophysiological techniques were used to assess CB1 receptor-mediated signalling.
KEY RESULTS Expressed in autaptic hippocampal neurones cultured from CB1-/- mice, hCB(1), hCB(1a) and hCB(1b) signal differentially from one another and from rodent CB1 receptors. Specifically, hCB(1) receptors inhibit synaptic transmission less effectively than rCB(1) receptors.
CONCLUSIONS AND IMPLICATIONS Our results suggest that cannabinoid receptor signalling in humans is quantitatively very different from that in rodents. As the problems of marijuana and hashish abuse occur in humans, our results highlight the importance of studying hCB(1) receptors. They also suggest further study of the distribution and function of hCB(1) receptor splice variants, given their differential signalling and potential impact on human health.

• 出版日期2012-4