Extracellular protons differentially potentiate the responses of native AMPA receptor subtypes regulating neurotransmitter release

Abstract

1 The effects of pH changes on the basal and evoked release of [³H]noradrenaline ([³H]NA) and [³H]5‐hydrohytryptamine ([³H]5‐HT) from hippocampal synaptosomes and of [³H]dopamine ([³H]DA) and [³H]acetylcholine ([³H]ACh) from striatal and cortical synaptosomes were investigated in rat brain. 2 Changing pH between 6.4 and 8.0 did not affect the spontaneous release of the four [³H]neurotransmitters; alkalinization to pH 8.8 significantly enhanced release. Acidification to pH 6.4 augmented the AMPA‐evoked overflows of [³H]NA, [³H]5‐HT and [³H]DA, but not that of [³H]ACh. In contrast, lowering pH to 6.4 decreased the K⁺‐evoked overflows of [³H]NA, [³H]5‐HT, [³H]DA and [³H]ACh. 3 AMPA released transmitters in a Ca²⁺‐dependent, exocytotic manner since its effects, at pH 7.4 or 6.4, were abolished by omitting external Ca²⁺ or by depleting vesicular transmitter stores with bafilomycin A1. AMPA did not evoke carrier‐mediated release because the uptake blockers nisoxetine, 6‐nitroquipazine, GBR12909 and hemicholinium‐3 could not inhibit the AMPA‐induced release of [³H]NA, [³H]5‐HT, [³H]DA and [³H]ACh. 4 Extraterminal acidification to pH 6.4 prevented the potentiating effect of cyclothiazide on the AMPA‐evoked release of [³H]NA, [³H]DA and [³H]5‐HT, whereas the proton‐insensitive AMPA‐evoked release of [³H]ACh, previously found to be cyclothiazide‐insensitive at pH 7.4 was cyclothiazide‐resistant also at pH 6.4. 5 To conclude, the cyclothiazide‐sensitive AMPA receptors mediating release of NA, 5‐HT and DA, but not the cyclothiazide‐insensitive AMPA receptors mediating the release of ACh, become more responsive when external pH is lowered to pathophysiologically relevant values. The results with cyclothiazide suggest that H⁺ ions may prevent desensitization of some AMPA receptor subtypes. British Journal of Pharmacology (2005) 144, 293–299. doi:10.1038/sj.bjp.0705960