Unconventional GPCR Signaling May Affect Synaptic Function

By studying G protein–coupled receptors (GPCRs) in mouse hippocampal slices, Qi Ding and colleagues provide evidence of unconventional receptor signaling that has implications for the function of synapses in the brain. When bound by their ligands outside of cells, GPCRs activate distinct signaling pathways that depend on which G proteins they couple to. GPCRs that couple to G_s or G_i proteins respectively stimulate or inhibit enzymes called adenylyl cyclases (ADCYs). These interactions lead to either increased or decreased amounts of a signaling molecule called cAMP. Meanwhile, GPCRs that couple to G_q proteins activate phospholipase enzymes to generate intracellular calcium ions (Ca²⁺). Ding et al. took slices of the hippocampus from mouse brains and measured responses to the stimulation of muscarinic acetylcholine receptors or metabotropic glutamate receptors that couple to G_q proteins. They found that the stimulation of these receptors led to the expected increases in Ca²⁺, and that cAMP abundance and signaling also rose. The Ca²⁺ generated by these receptors triggered the activation of Ca²⁺-dependent ADCY1 and ADCY8, which generated the cAMP. In contrast, hippocampal slices from mice deficient in ADCY1 and ADCY8 did not exhibit cAMP signaling when the researchers stimulated G_q-coupled GPCRs. In addition, the slices showed impaired long-term depression (LTD), a process where synaptic function in neurons diminishes after repeated stimulation. Together, these data suggest that G_q-coupled GPCRs modulate synaptic function in a cAMP-dependent manner, providing evidence of crosstalk in signaling pathways that regulate neuronal function.