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G protein coupled receptors (GPCRs) play a key role in the vast majority of cellular signal transduction processes. Previous experimental evidence has shown that sodium ion (Na + ) allosterically modulate several class A GPCRs and theoretical studies suggested that the same also holds true for muscarinic receptors. Here we examined, using Xenopus oocytes as an expression system, the effect of Na +  on a prototypical GPCR, the M2 muscarinic receptor (M2R). We found that removal of extracellular Na +  resulted in a decrease in the potency of ACh toward the M2R and that a conserved aspartate in transmembrane domain 2 is crucial for this effect. We further show that this allosteric effect of Na +  does not underlie the voltage-dependence of this receptor.

Sodium ions allosterically modulate the M2 muscarinic receptor