Gq-coupled receptors raise cAMP via ADCY1 and ADCY8 in mouse hippocampal slices
Qi Ding's team found that Gq-coupled receptors, stimulated in mouse hippocampal slices, raise cAMP as well as calcium, with consequences for synaptic long-term depression.
Qi Ding and colleagues studied G protein–coupled receptors (GPCRs) in hippocampal slices from mice and reported evidence of unconventional receptor signaling with implications for synaptic function in the brain, according to eurekalert.org eurekalert.org
eurekalert.orgeurekalert.orgOpen source ↗. The experiments were carried out on mouse brain tissue slices. Stimulation of Gq-coupled receptors raised cAMP in addition to calcium ions.
How GPCRs normally signal
When GPCRs are bound by ligands outside cells, they activate distinct signaling pathways that depend on the G proteins they couple to. Receptors coupled to Gs or Gi proteins respectively stimulate or inhibit enzymes called adenylyl cyclases (ADCYs). These interactions increase or decrease the amount of the signaling molecule cAMP.
Receptors coupled to Gq proteins follow a different route: they activate phospholipase enzymes to generate intracellular calcium ions (Ca2+). Ding and colleagues measured how these receptors behave in brain tissue.
Calcium-driven cAMP production
The team stimulated muscarinic acetylcholine receptors or metabotropic glutamate receptors, both of which couple to Gq proteins, in the slices. Ca2+ increased as expected, but cAMP abundance and cAMP signaling also rose. eurekalert.org
eurekalert.orgeurekalert.orgOpen source ↗ The Ca2+ generated by these receptors activated the Ca2+-dependent enzymes ADCY1 and ADCY8, which produced the cAMP.
In hippocampal slices from mice deficient in ADCY1 and ADCY8, stimulating Gq-coupled GPCRs did not produce cAMP signaling. These slices also showed impaired long-term depression (LTD), a process in which synaptic function in neurons diminishes after repeated stimulation.
The authors say the data suggest that Gq-coupled GPCRs modulate synaptic function in a cAMP-dependent manner. They describe this as evidence of crosstalk between signaling pathways that regulate neuronal function.
