Cho K, Brown M W, Bashir Z I
MRC Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, Bristol BS8 1TD, UK.
J Physiol. 2002 May 1;540(Pt 3):895-906. doi: 10.1113/jphysiol.2001.013920.
In this study we have investigated mechanisms underlying enhancement by group II metabotropic glutamate (mGlu) receptors of group I mGlu receptor-induced calcium mobilization. Inhibition of protein kinase A (PKA) caused an enhancement of mGlu5 receptor-mediated calcium mobilization and occluded the enhancement by group II mGlu receptors. A peptide (Ht31) that prevents interaction between A-kinase anchoring protein (AKAP) and PKA also enhanced mGlu5-mediated calcium mobilization. Enhancement of mGlu5 function, by inhibition of PKA or by activation of group II mGlu receptors, was prevented by the protein phosphatase 2B (PP2B) inhibitor cyclosporin A. Furthermore, the enhancement by activation of group II mGlu receptors was prevented by raising intracellular cAMP. These results suggest that the regulation by PKA and PP2B of phosphorylation of a substrate on mGlu5 and/or on group II mGlu receptors is intimately involved in the mechanisms underlying interaction between group II mGlu and mGlu5 receptors. Long-term depression (LTD) in perirhinal cortex requires group I, group II and NMDA receptor activation at resting membrane potentials but does not require group II mGlu receptor activation at depolarized potentials. We previously suggested that interaction between group I and group II mGlu receptors is required for induction of LTD at resting potentials. In support of this, we demonstrate in perirhinal cortex slices that blocking mechanisms underlying mGlu receptor synergy (by raising intracellular cAMP or by inhibition of PP2B) selectively prevented LTD at resting membrane potentials. This study thus provides a potential explanation for the co-requirement in LTD of group I and group II mGlu receptor activation. Similar mechanisms of synergistic interaction may also be important in other physiological processes dependent on mGlu receptors.
在本研究中，我们探究了II组代谢型谷氨酸（mGlu）受体增强I组mGlu受体诱导的钙动员的潜在机制。蛋白激酶A（PKA）的抑制增强了mGlu5受体介导的钙动员，并消除了II组mGlu受体的增强作用。一种阻止A激酶锚定蛋白（AKAP）与PKA相互作用的肽（Ht31）也增强了mGlu5介导的钙动员。蛋白磷酸酶2B（PP2B）抑制剂环孢素A可阻止通过抑制PKA或激活II组mGlu受体对mGlu5功能的增强。此外，提高细胞内cAMP可阻止II组mGlu受体激活所产生的增强作用。这些结果表明，PKA和PP2B对mGlu5和/或II组mGlu受体上底物磷酸化的调节密切参与了II组mGlu与mGlu5受体相互作用的潜在机制。嗅周皮质的长时程抑制（LTD）在静息膜电位时需要I组、II组和NMDA受体激活，但在去极化电位时不需要II组mGlu受体激活。我们之前曾提出，I组和II组mGlu受体之间的相互作用是静息电位时LTD诱导所必需的。为此，我们在嗅周皮质切片中证明，阻断mGlu受体协同作用的潜在机制（通过提高细胞内cAMP或抑制PP2B）可选择性地阻止静息膜电位时的LTD。因此，本研究为I组和II组mGlu受体激活在LTD中的共同需求提供了一种潜在解释。类似的协同相互作用机制在其他依赖mGlu受体的生理过程中可能也很重要。
