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

While 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-mediated inhibition of inhibitory postsynaptic currents (IPSCs) recorded in mouse proopiomelanocortin (POMC) neurons exhibit acute desensitization in ~25% of experiments. To determine if differential effector coupling confers sensitivity to desensitization, voltage-clamp recordings were made from POMC neurons to compare the mechanisms by which mu 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. Further, since both the desensitizing and non-desensitizing presynaptic receptors are similarly coupled, differential effector coupling is unlikely responsible for differential desensitization of the inhibition of release.

from Physiology via xlomafota13 on Inoreader http://ift.tt/1VG4EP1
via IFTTT