Allosteric potentiators of metabotropic glutamate receptor subtype 1a differentially modulate independent signaling pathways in baby hamster kidney cells.
Recent studies suggest that subtype specific activators of metabotropic glutamate receptors (mGluRs) have exciting potential for the development of novel treatment strategies for numerous psychiatric and neurological disorders. A number of positive allosteric modulators (PAMs) have been identified that are highly selective for mGluR1, including the compounds Ro 01-6128, Ro 67-4853, and Ro 67-7476. These PAMs have been previously found to interact with a site distinct from that of negative allosteric modulators (NAMs), typified by R214127. These mGluR1 PAMs do not have an effect on baseline calcium levels but induce leftward shifts in the concentration-response of mGluR1 to agonists. However, their effects on a variety of signaling pathways and their mechanism of action have not been fully explored and are of critical importance for further development of mGluR1 allosteric modulators as novel drugs. In baby hamster kidney (BHK) cells, mGluR1 activates calcium mobilization, cAMP production, and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation; signaling cascades which are distinct and differentially regulated. In contrast to their effects on calcium mobilization, these compounds were found to activate ERK1/2 phosphorylation in the absence of exogenously added agonist, an effect that was fully blocked by both orthosteric (LY341495) and allosteric (R214127) mGluR1 antagonists. The mGluR1 PAMs were also found to activate cAMP production in the absence of agonist. Thus, these mGluR1 PAMs have qualitatively different effects on a variety of mGluR1-mediated signal transduction cascades. Together, these data provide further evidence that allosteric compounds can differentially modulate the coupling of a single receptor to independent signaling pathways or act in a system-dependent manner.
Sheffler
Douglas J
DJ
Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
Conn
P Jeffrey
PJ
D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002461:Cell Line, Transformed; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011714:Pyrans / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000378:metabolism; D014966:Xanthenes / Q000494:pharmacology
D000596:Amino Acids; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D011714:Pyrans; D011804:Quinolines; C473784:R 214127; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C104077:metabotropic glutamate receptor type 1; D014316:Tritium; D018698:Glutamic Acid; D000242:Cyclic AMP; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium