Structure and function of Cannabinoid Receptor Heterodimers

G protein-coupled receptors (GPCR) function via conformational change in response to ligand binding resulting in dynamic protein-protein interactions. Multiple type A GPCR physically associate in heteromeric complexes and the signalling response to ligand binding is dependent on the GPCRs in the complex. Given the differential coupling of GPCRs in different cell types, the response to endogenous ligands and neurotransmitters in different brain regions is more complex than imagined previously. There is a growing interest in understanding the unique properties of heteromers containing cannabinoid receptors in complex with other GPCRs including other cannabinoid receptors, dopamine receptors, adenosine receptors and opioid receptors. The signalling of heteromeric complexes in response to endogenous ligands such as endocannabinoids depends on the relative concentration of receptors, proportion of receptors involved in heteromeric complexes and the local concentration of endogenous ligands. The work proposed is part of a long-term research program to understand how heteromeric GPCRs control basic homeostatic processes including modulation of neurotransmission, neurogenesis, cerebral vascular function and immune responses in the periphery and in the brain. The results of this research program will provide novel information on the function of the ECS, which is now recognized as a major neuro- and immunomodulator for the mammalian brain. Specifically, we will contribute the understanding of the complex regulation of the neurovascular boundary between the brain and periphery during normal development, aging, and during periods of inflammation.