Molecular and Cellular Endocrinology
Signaling via CNS cannabinoid receptors
Introduction
The primary cannabinoid receptors in the CNS are CB1 receptors. The CB1 receptor is a member of the large family of G protein-coupled receptors (GPCRs) (Howlett et al., 2002). Thus, they are cell surface proteins that consist of seven transmembrane domains, with an extracellular amino terminus, and an intracellular C terminus. CB1 receptors predominately couple to inhibitory G proteins (Gi and Go), but under certain conditions they can couple to either Gs or Gq/11 (Howlett et al., 2002). Coupling to Gi and Go means that the primary effects of CB1 activation are inhibition of adenylyl cyclase and certain calcium channels together with the activation of inwardly rectifying potassium channels and several different MAP kinases (Howlett et al., 2002). A second cannabinoid receptor is the CB2 cannabinoid receptor. Although this receptor is primarily found in cells of the immune system, credible data support the expression of CB2 in neurons under certain circumstances (Van Sickle et al., 2005, Wotherspoon et al., 2005). However, while its biology is fascinating (Whiteside et al., 2007) a consideration of this receptor is beyond the scope of the current review. There are additional receptors that can interact with exogenous and endogenous cannabinoids, including GPR55 (Pertwee, 2007). Whether these receptors play a role in modulating neurotransmission remains controversial (Hajos and Freund, 2002, Hoffman et al., 2005, Takahashi and Castillo, 2006) and will not be considered here.
Section snippets
Cannabinoid receptor localization
Key to understanding the function of a receptor is determining its localization. CB1 receptors have been localized by autoradiography, in situ hybridization, and immunocytochemistry reviewed by Mackie (2005). These studies reveal several interesting properties of CB1 receptors and their distribution. The first is that CB1 receptors are among the most abundant GPCRs in the central nervous system (Herkenham et al., 1990). The second is that the pattern of CB1 receptor expression is consistent
Endogenous cannabinoids (endocannabinoids)
The presence of cannabinoid receptors suggests an endogenous ligand. Indeed, this is the case. Two endogenous ligands for the CB1 receptor have been well characterized. The first is anandamide, the amide of arachidonic acid and ethanolamine (Devane et al., 1992). The second is 2-arachidonoyl glycerol (2-AG), the ester (at the sn two position) of arachidonic acid and glycerol (Stella et al., 1997, Sugiura et al., 1995). Both share the similarity that they exist as precursors in the cell membrane
Endocannabinoid-mediated synaptic plasticity
As mentioned above, the majority of CB1 receptors are found presynaptically. While the highest levels in forebrain are found on CCK positive interneurons (Katona et al., 1999), they are also present on many forebrain glutamatergic terminals (Katona et al., 2006, Kawamura et al., 2006). Activation of presynaptic CB1 receptors decreases neurotransmitter release, an effect first demonstrated unequivocally in cultured hippocampal neurons (Shen et al., 1996). Since endocannabinoids are synthesized
Interactions between Δ9THC and endocannabinoid-mediated synaptic plasticity
The last several years have seen the emergence of an, albeit partial, understanding of the multiple roles endocannabinoids play in modulating synaptic transmission and neuronal excitability. An important question for the field is how Δ9THC (THC), the primary psychoactive component of cannabis interacts with these multiple forms of plasticity. That is, what underlies the psychoactivity of cannabis? Two broad possibilities might be the explanation. The first is that since THC is an agonist at CB1
Conclusions and perspectives
The past 20 years have seen the emergence of the endocannabinoid system from the receptors “hijacked” by cannabis to a complex neuromodulatory system involved in processes as diverse as cognition, reinforcement, energy balance and reproduction. Endocannabinoids mediate several forms of synaptic plasticity, an action that may underlie their varied psychoactive and behavioral actions. In addition to the diverse processes influenced by the endocannabinoid system, it is becoming increasingly
Acknowledgements
I would like to thank my collaborators and colleagues for their comments and experiments that have shaped many of the ideas presented here. Funding has been provided by NIH grants DA11322 and DA021696
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