Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the β2-adrenoceptor

G-PROTEIN-COUPLED receptors are thought to have an inactive conformation (R), requiring an agonist-induced conformational change for receptor/G-protein coupling1–3. But new evidence suggests a two-state model4–19 in which receptors are in equilibrium between the inactive conformation (R), and a spontaneously active conformation (R*) that can couple to G protein in the absence of ligand (Fig. 1). Classic agonists have a high affinity for R* and increase the concentration of R*, whereas inverse agonists have a high affinity for R and decrease the concentration of R*. Neutral competitive antagonists have equal affinity for R and R* and do not displace the equilibrium, but can competitively antagonize the effects both of agonists and of inverse agonists. The lack of suitable in vivo model systems has restricted the evidence for the existence of inverse agonists to computer simulations7,8 and in vitro systems5,9–12,20–23. We have used a transgenic mouse model in which there is such marked myocardial overexpression of β2-adrenoceptors that a significant population of spontaneously activated receptor (R*) is present, inducing a maximal response without agonist24. We show that the β2-adrenoceptor ligand ICI-118,551 functions as an inverse agonist, providing evidence supporting the existence of inverse agonists and validating the two-state model of G-protein-coupled receptor activation

The molecular logic of endocannabinoid signalling

The endocannabinoids are a family of lipid messengers that engage the cell surface receptors that are targeted by Δ9-tetrahydrocannabinol, the active principle in marijuana (Cannabis). They are made on demand through cleavage of membrane precursors and are involved in various short-range signalling processes. In the brain, they combine with CB1 cannabinoid receptors on axon terminals to regulate ion channel activity and neurotransmitter release. Their ability to modulate synaptic efficacy has a wide range of functional consequences and provides unique therapeutic possibilities. © 2003, Nature Publishing Group. All rights reserved