Endocannabinoid signaling pathways: beyond CB1R and CB2R

Area of Science:

• Pharmacology
• Neuroscience
• Molecular Biology

Background:

• The endocannabinoid system, primarily involving cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), plays crucial roles in physiological processes.
• The existence of additional cannabinoid receptors beyond CB1R and CB2R has been hypothesized.
• Identifying novel cannabinoid receptors could expand our understanding of the endocannabinoid system's functions and therapeutic potential.

Purpose of the Study:

• To systematically review and evaluate the evidence for seven proposed orphan receptors as novel cannabinoid receptors.
• To critically assess the phylogenetic and functional data supporting the inclusion of these receptors in the cannabinoid receptor family.
• To provide a comprehensive overview of the ongoing search for non-CB1R and non-CB2R cannabinoid receptors.

Main Methods:

• Literature review of studies investigating orphan receptors with proposed cannabinoid activity.
• Analysis of phylogenetic relationships between known and putative cannabinoid receptors.
• Evaluation of binding and signaling assays using endocannabinoids and phytocannabinoids against candidate receptors.

Main Results:

• Seven specific orphan receptors have been proposed as potential cannabinoid receptors.
• Evidence supporting their classification is based on evolutionary links and interactions with cannabinoids.
• Counterarguments and limitations of the current evidence for each receptor are presented.

Conclusions:

• The classification of these seven receptors as true cannabinoid receptors remains under investigation.
• Further rigorous research is required to definitively establish their role within the cannabinoid receptor family.
• The ongoing exploration highlights the complexity and evolving landscape of the endocannabinoid system.