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Related Concept Videos

Ligand Binding and Linkage00:49

Ligand Binding and Linkage

Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...
Ligand Binding and Linkage00:49

Ligand Binding and Linkage

Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...
The Two-State Receptor Model01:29

The Two-State Receptor Model

The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with one...
Opioid Receptors: Overview01:22

Opioid Receptors: Overview

Opioid receptors, including the mu (μ, MOR), delta (δ, DOR), and kappa (κ, KOR) types, belong to the rhodopsin family of G protein-coupled receptors. These receptors are located throughout the central and peripheral nervous systems and in non-neuronal tissues such as macrophages and astrocytes. Opioid receptor ligands can be categorized into agonists or antagonists. Highly selective agonists include [d-Ala2, MePhe4, Gly(ol)5]-enkephalin or DAMGO for MOR, [D-Pen2, D-Pen5]-enkephalin or DPDPE for...
Chemotherapy-Induced Nausea and Vomiting: Cannabinoids01:21

Chemotherapy-Induced Nausea and Vomiting: Cannabinoids

Tetrahydrocannabinol (THC) is a phytocannabinoid that primarily interacts with the CB1 receptor, a type of G protein-coupled receptor (GPCR) predominantly in and around the chemoreceptor trigger zone (CTZ) and emetic center. THC also blocks the serotonin receptor activity in the dorsal vagal complex (DVC) by inhibiting serotonin release. THC exerts its anti-emetic effects through these interactions, which are beneficial for patients undergoing chemotherapy.
Two synthetic agonists of THC,...
Drug-Receptor Interaction: Agonist01:25

Drug-Receptor Interaction: Agonist

Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous ligand's action.

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Related Experiment Video

Updated: Jul 14, 2026

Synthesis of a Deuterated Standard for the Quantification of 2-Arachidonoylglycerol in Caenorhabditis elegans
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Synthesis of a Deuterated Standard for the Quantification of 2-Arachidonoylglycerol in Caenorhabditis elegans

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Coevolution between cannabinoid receptors and endocannabinoid ligands.

John M McPartland1, Ryan W Norris, C William Kilpatrick

  • 1GW Pharmaceuticals, Middlebury, VT 05753, USA. mcpruitt@verizon.net

Gene
|June 1, 2007
PubMed
Summary

Cannabinoid receptors coevolved with fatty acid ester ligands, like 2-arachidonoyl glycerol (2-AG), before developing affinity for fatty acid ethanolamides, such as anandamide (AEA). This finding clarifies the intrinsic ligand debate.

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Last Updated: Jul 14, 2026

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Area of Science:

  • * Molecular Evolution
  • * Neuroscience
  • * Biochemistry

Background:

  • * Coevolution of receptor and ligand genes is crucial for maintaining biological functions.
  • * The debate on whether anandamide (AEA) or 2-arachidonoyl glycerol (2-AG) is the primary endogenous ligand for cannabinoid receptors (CB1, CB2) remains unresolved.

Purpose of the Study:

  • * To resolve the debate regarding the intrinsic ligand of cannabinoid receptors through coevolutionary analysis.
  • * To investigate the evolutionary history of CB1, CB2 receptors and their associated metabolic enzymes.

Main Methods:

  • * Comparative genomics and phylogenetic analysis of CB1, CB2, and ten metabolic enzyme genes across nine diverse species.
  • * Construction of gene trees (cladograms) and phylograms using Bayesian inference and maximum likelihood methods.
  • * Correlation analysis of phylogram branch lengths to assess coevolutionary relationships.

Main Results:

  • * Mirrored cladograms indicated parallel cladogenesis, providing evidence of coevolution between cannabinoid receptors and ligand metabolic enzymes.
  • * Regression analyses and phylogenetic profiling revealed a close evolutionary association between cannabinoid receptors and diacylglycerol lipase (DAGL) enzymes.
  • * The study identified specific DAGL paralogs as key coevolving partners of cannabinoid receptors.

Conclusions:

  • * Cannabinoid receptors likely coevolved initially with fatty acid ester ligands, structurally similar to 2-AG, in early metazoans.
  • * The affinity for fatty acid ethanolamide ligands, such as AEA, appears to have evolved subsequently.
  • * This research provides a novel evolutionary perspective on the cannabinoid system and its ligand interactions.