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

Whereas the activation of Gα_i/o-coupled receptors commonly results in postsynaptic responses that show acute desensitization, the presynaptic inhibition of transmitter release caused by many Gα_i/o-coupled receptors is maintained during agonist exposure. However, an exception has been noted where GABA_B receptor (GABA_BR)-mediated inhibition of inhibitory postsynaptic currents (IPSCs) recorded in mouse proopiomelanocortin (POMC) neurons exhibit acute desensitization in ~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 μ-opioid receptors (MORs) and GABA_BRs inhibit transmitter release. Neither MOR- nor GABA_BR-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_BRs 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.

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