| The cannabinoid and beta-adrenergic systems carry out diverse functions both within the central nervous system and periphery. Each of these two systems utilize G protein coupled receptors (GPCRs) to generate their biological effects. GPCRs represent the largest family of signal transduction proteins and are the most common molecular targets for currently available therapeutics. There is now a strong body of evidence that GPCRs can interact with each other as dimers or higher order oligomers, and that these interactions influence the function of these receptors. Cannabinoid and beta-adrenergic receptors are co-expressed in a variety of tissues and organs including the cardiovascular system, brain, bone, female reproductive tract and eye. Therefore, the present work examined the possibility of interactions between cannabinoid and beta-adrenergic receptors. Heterodimerization between the CB1 cannabinoid receptor and the beta2-adrenergic receptor (beta2AR) was demonstrated in a HEK 293H expression system. This interaction between CB 1 and beta2AR was shown to affect constitutive activity, agonist-induced trafficking, as well as the signalling pathways of these two receptors. To examine the potential significance of this interaction in vivo, CB1 and beta2AR signalling pathways were assessed in ocular trabecular meshwork cells that are known to endogenously co-express these two receptors. Human trabecular meshwork (HTM) cells are involved in the outflow of aqueous humor and regulation of intraocular pressure (IOP). Functional interactions between CB1 and beta2AR, similar to those identified in the HEK 293H expression system, were also observed in HTM cells. Finally, as drugs acting on the cannabinoid system (agonists) and beta-adrenergic system (antagonists) are known to reduce IOP in vivo, interactions between these two systems in the regulation of IOP were examined in mice. These experiments demonstrated functional interactions between the cannabinoid and beta-adrenergic systems in the regulation of IOP. Taken together, the results of this thesis have identified novel physical and functional interactions between cannabinoid and beta-adrenergic receptors in cells heterologously or endogenously expressing these receptors and demonstrated that interactions between these receptors are relevant in vivo in the regulation of IOP. |
