Desensitization-resistant and -sensitive GPCR-mediated inhibition of GABA release occurs by Ca2+-dependent and -independent mechanisms at a hypothalamic synapse

作者：Pennock Reagan L; Hentges Shane T^*

来源：Journal of Neurophysiology, 2016, 115(5): 2376-2388.

DOI：10.1152/jn.00535.2015

• mu opioid receptor
• GABA(B) receptor
• POMC
• calcium
• strontium

Whereas the activation of G alpha(i/o) coupled receptors commonly results in postsynaptic responses that show acute desensitization, the presynaptic inhibition of transmitter release caused by many G alpha(i/o)-coupled receptors is maintained during agonist exposure. However, an exception has been noted where GABA(B) receptor (GABA(B)R)-mediated inhibition of inhibitory postsynaptic currents (IPSCs) recorded in mouse proopiomelanocortin (POMC) neurons exhibit acute desensitization in similar to 25% of experiments. To determine whether differential effector coupling confers sensitivity to desensitization, voltage-clamp recordings were made from POMC neurons to compare the mechanism by which mu-opioid receptors (MORs) and GABA(B)Rs inhibit transmitter release. Neither MOR-nor GABA(B)R-mediated inhibition of release relied on the activation of presynaptic K+ channels. Both receptors maintained the ability to inhibit release in the absence of external Ca2+ or in the presence of ionomycin-induced Ca2+ influx, indicating that inhibition of release can occur through a Ca2+ independent mechanism. Replacing Ca2+ with Sr2+ to disrupt G-protein-mediated inhibition of release occurring directly at the release machinery did not alter MOR-or GABA(B) -mediated inhibition of IPSCs, suggesting that reductions in evoked release can occur through the inhibition of Ca2+ channels. Additionally, both receptors inhibited evoked IPSCs in the presence of selective blockers of N-or P/Q-type Ca2+ channels. Altogether, the results show that MORs and GABA(B)Rs can inhibit transmitter release through the inhibition of calcium influx and by direct actions at the release machinery. Furthermore, since both the desensitizing and nondesensitizing presynaptic receptors are similarly coupled, differential effector coupling is unlikely responsible for differential desensitization of the inhibition of release.

• 出版日期2016-5