A Systematic Review of Inverse Agonism at Adrenoceptor Subtypes.

As many, if not most, ligands at G protein-coupled receptor antagonists are inverse agonists, we systematically reviewed inverse agonism at the nine adrenoceptor subtypes. Except for β-adrenoceptors, inverse agonism has been reported for each of the adrenoceptor subtypes, most often for β-adrenoceptors, including endogenously expressed receptors in human tissues. As with other receptors, the detection and degree of inverse agonism depend on the cells and tissues under investigation, i.

Desensitization of cAMP Accumulation via Human β3-Adrenoceptors Expressed in Human Embryonic Kidney Cells by Full, Partial, and Biased Agonists.

β-Adrenoceptors couple not only to cAMP formation but, at least in some cell types, also to alternative signaling pathways such as phosphorylation of extracellular signal-regulated kinase (ERK). β-Adrenoceptor agonists are used in long-term symptomatic treatment of the overactive bladder syndrome; it is only poorly understood which signaling pathway mediates the clinical response and whether it undergoes agonist-induced desensitization. Therefore, we used human embryonic kidney cells stably transfected with human β-adrenoceptors to compare coupling of ligands with various degrees of efficacy, including biased agonists, to cAMP formation and ERK phosphorylation, particularly regarding desensitization.

Muscarinic type-1 receptors contribute to I in human atrial cardiomyocytes and are upregulated in patients with chronic atrial fibrillation.

Background: Basal and acetylcholine-gated inward-rectifier K-currents (I and I, respectively) are altered in atrial fibrillation (AF). G-protein-coupled muscarinic (M) receptors type-2 are considered the predominant receptors activating I. Although a role for G-coupled non-M-receptor subtypes has been suggested, the precise regulation of I by multiple M-receptor subtypes in the human atrium is unknown.

The new radioligand [(3)H]-L 748,337 differentially labels human and rat β3-adrenoceptors.

As no suitable radioligand exists for the detection of β3-adrenoceptors, we have explored the radioligand binding properties of a tritiated version of the selective β3-adrenoceptor antagonist L 748,337. Kinetic and equilibrium saturation and competition binding experiments were performed with [(3)H]-L 748,337 on membrane fractions of HEK and CHO cells stably transfected with human and rat β-adrenoceptor subtypes. Based on both association/dissociation kinetic and equilibrium saturation binding studies in transfected HEK cells, [(3)H]-L 748,337 exhibited an affinity of approximately 2 nM for human β3-adrenoceptors.

Agonist-induced desensitization of human β3-adrenoceptors expressed in human embryonic kidney cells.

β3-Adrenoceptors are resistant to agonist-induced desensitization in some cell types but susceptible in others including transfected human embryonic kidney (HEK) cells. Therefore, we have studied cellular and molecular changes involved in agonist-induced β3-adrenoceptor desensitization in HEK cells. Cells were treated with isoprenaline or forskolin, and following wash-out, cyclic adenosine monophosphate (cAMP) accumulation in response to freshly added agonist was quantified.

The muscarinic receptor antagonist propiverine exhibits α(1)-adrenoceptor antagonism in human prostate and porcine trigonum.

Purpose: Combination therapy of male lower urinary tract symptoms with α(1)-adrenoceptor and muscarinic receptor antagonists attracts increasing interest. Propiverine is a muscarinic receptor antagonist possessing additional properties, i.e.

Lack of evidence that nebivolol is a β₃-adrenoceptor agonist.

Nebivolol is a selective β₁-adrenoceptor antagonist which, in addition, displays endothelium-dependent vasodilating properties in humans and other species. β₃-adrenoceptors have been proposed to be a molecular target of nebivolol-induced vasodilatation. Therefore, we have investigated possible β₃-adrenoceptor agonism by nebivolol for relaxation of the human and rat urinary bladder (prototypical β₃-adrenoceptor-mediated responses) as well as for cAMP accumulation in Chinese hamster ovary cells stably transfected with the human β-adrenoceptor subtypes.

WITHDRAWN: Is nebivolol a beta(3)-adrenoceptor agonist?

This article has been withdrawn at the request of the authors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.

Comparison of three radioligands for the labelling of human beta-adrenoceptor subtypes.

We have compared the ability of three radioligands, [(125)I]-cyanopindolol, [(3)H]-CGP 12,177 and [(3)H]-dihydroalprenolol, to label the three human beta-adrenoceptor subtypes. Saturation and competition binding experiments were performed using membrane preparations from Chinese hamster ovary cells stably transfected with the three subtypes. While [(3)H]-CGP 12,177 had very similar affinity for beta(1)- and beta(2)-adrenoceptors (about 40 pM), [(125)I]-cyanopindolol and [(3)H]-dihydroalprenolol had 4- to 6-fold higher affinity for beta(2)- as compared to beta(1)-adrenoceptors (10 vs 45 and 187 vs 1,021 pM, respectively).

Effects of ageing on muscarinic receptor subtypes and function in rat urinary bladder.

We compared the density and function of M2 and M3 muscarinic acetylcholine receptor subtypes in the urinary bladder of young adult (3 months) and old (23 months) male Wistar rats. Old rats had a reduced density of muscarinic receptors (96+/-10 vs. 156+/-21 fmol/mg protein), but competition experiments with the M3-selective darifenacin did not indicate alterations in the relative roles of M2 and M3 receptors, with the former being more abundant.