Functional selectivity induced by mGlu₄ receptor positive allosteric modulation and concomitant activation of G_q coupled receptors

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• 作者：Shen Yin ; Rocio Zamorano ; P. Jeffrey Conn ; Colleen M. Niswender ; ^{Colleen.niswender@vanderbilt.edu}
• 关键词：Glutamate ; Histamine ; Receptor ; Allosteric modulator ; Functional selectivity
• 刊名：Neuropharmacology
• 出版年：2013
• 出版时间：March, 2013
• 年：2013
• 卷：66
• 期：Complete
• 页码：122-132
• 全文大小：689 K

文摘

Metabotropic glutamate receptors (mGlus) are a group of Family C Seven Transmembrane Spanning Receptors (7TMRs) that play important roles in modulating signaling transduction, particularly within the central nervous system. mGlu₄ belongs to a subfamily of mGlus that is predominantly coupled to G_i/o G proteins. We now report that the ubiquitous autacoid and neuromodulator, histamine, induces substantial glutamate-activated calcium mobilization in mGlu₄-expressing cells, an effect which is observed in the absence of co-expressed chimeric G proteins. This strong induction of calcium signaling downstream of glutamate activation of mGlu₄ depends upon the presence of H₁ histamine receptors. Interestingly, the potentiating effect of histamine activation does not extend to other mGlu₄-mediated signaling events downstream of G_i/o G proteins, such as cAMP inhibition, suggesting that the presence of G_q coupled receptors such as H₁ may bias normal mGlu₄-mediated G_i/o signaling events. When the activity induced by small molecule positive allosteric modulators of mGlu₄ is assessed, the potentiated signaling of mGlu₄ is further biased by histamine toward calcium-dependent pathways. These results suggest that G_i/o-coupled mGlus may induce substantial, and potentially unexpected, calcium-mediated signaling events if stimulation occurs concomitantly with activation of G_q receptors. Additionally, our results suggest that signaling induced by small molecule positive allosteric modulators may be substantially biased when G_q receptors are co-activated.

This article is part of a Special Issue entitled ¡®Metabotropic Glutamate Receptors¡¯.