Group I metabotropic glutamate (mGlu) receptors regulate hippocampal CA1 pyramidal neuron excitability via Ca 2ϩ wave-dependent activation of small-conductance Ca 2ϩ -activated K ϩ (SK) channels. Here, we show that mGlu 5 receptors and SK2 channels coassemble in heterologous coexpression systems and in rat brain. Further, in cotransfected cells or rat primary hippocampal neurons, mGlu 5 receptor stimulation activated apamin-sensitive SK2-mediated K ϩ currents. In addition, coexpression of mGlu 5 receptors and SK2 channels promoted plasma membrane targeting of both proteins and correlated with increased mGlu 5 receptor function that was unexpectedly blocked by apamin. These results demonstrate a reciprocal functional interaction between mGlu 5 receptors and SK2 channels that reflects their molecular coassembly.
Besides some pharmacological, biochemical and biophysical evidences support the contention that muscarinic acetylcholine receptors can form homo- and heterodimers, the existence of specific M(3) and M(5) muscarinic receptors oligomers in living cells is a new concept. Interestingly, this phenomenon might have relevance in lymphocytic cholinergic function since both T- and B-cells naturally express high levels of these two receptor subtypes. Here, by means of co-immunoprecipitation and bioluminescence resonance energy transfer methods we demonstrated that M(3) and M(5) muscarinic receptors could form constitutive homo- and heterodimers in transiently transfected HEK-293T cells. Interestingly, this receptor-receptor interaction was unaltered by carbachol treatment but it was affected by the expression of a peptide corresponding to a portion of the third intracellular loop of the M(5) muscarinic receptor. In addition, the same peptide was able to abrogate the carbachol-induced mitogen-activated protein kinase phosphorylation and the carbachol-enhanced PHA-induced IL-2 production in derived lymphocytic T cells. Overall, these results suggest that the third intracellular loop of the M(5) muscarinic receptor might play a regulatory role in receptor function and heteromerization, thus providing the molecular framework for a potential cholinergic-based therapeutic intervention of the immune system.
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