Na⁺/H⁺ exchanger inhibition modifies dopamine neurotransmission during normal and metabolic stress conditions

Abstract

Na+/H+ exchanger (NHE) proteins are involved in intracellular pH and volume regulation and may indirectly influence neurotransmission. The abundant NHE isoform 1 (NHE1) has also been linked to brain cell damage during metabolic stress. It is not known, however, whether NHE1 or other NHE isoforms play a role in striatal dopamine (DA) neurotransmission under normal or metabolic stress conditions. Our study tested the hypothesis that NHE inhibition with cariporide mesilate (HOE-642) modifies striatal DA overflow and DAergic terminal damage in mice caused by the mitochondrial inhibitor malonate. We also explored the expression of NHE1–5 in the striatum and substantia nigra. Reverse microdialysis of HOE-642 elicited a transient elevation followed by a reduction in DA overflow accompanied by a decline in striatal DA content. HOE-642 pre-treatment diminished the malonate-induced DA overflow without reducing the intensity of the metabolic stress or subsequent DAergic axonal damage. Although NHE isoforms 1–5 are expressed in the striatum and midbrain, NHE1 protein was not co-located on nigrostriatal DAergic neurons. The absence of NHE1 co-location on DAergic neurons suggests that the effects of HOE-642 on striatal DA overflow are either mediated via NHE1 located on other cell types or that HOE-642 is acting through multiple NHE isoforms.

Cross‐reactivity of acid‐sensing ion channel and Na+–H+ exchanger antagonists with nicotinic acetylcholine receptors

“…This is supported by the observation that bath application of zoniporide completely blocked neurotransmission. In the CNS, glutamatergic nerve terminals express functional Na + -H + exchangers (Trudeau et al 1999;Rocha et al 2008), and studies in dissociated hippocampal neurones and cerebellar granule cells indicate that GABAergic presynaptic terminals also have such a pH regulatory system (Jang et al 2006;Dietrich & Morad, 2010). Our results show that inhibition of NHE1 with zoniporide blocks synaptic neurotransmission to the same extent as TTX, bicuculline and CdCl 2 , indicating that this ion exchanger is critical for neurotransmitter release.…”

“…NHE1 is ubiquitously expressed in vertebrates (Rocha et al 2008), and Western blot analysis of mouse MHb extracts confirmed the presence of NHE1 in this brain region (Fig. S1).…”

“…The effect of zoniporide on neurotransmission was also found not to be dependent on either glutamatergic or GABAergic receptors, as we did not observe any changes in evoked responses after direct somatic application of glutamate and GABA during perfusion with zoniporide. We speculate that the observed depression of neurotransmission could result from inhibition of NHE at presynaptic terminals, because NHE inhibitors have been reported to modify synaptic communication, regulate the activity of presynaptic nerve terminals and influence neurotransmitter release (Rocha et al 2008;Dietrich & Morad, 2010). Our results demonstrating a contribution of NHE1 to synaptic transmission in MHb neurones together with the potential contribution of NHEs to pathological extracellular acidification, such as hypoxia, ischaemia and hypoglycaemia (Katsura & Siesjo, 1998), are of particular interest in light of the observation that the habenula is highly vulnerable to hypoxia (Nakajima et al 2000).…”

“…NHE1 not only regulates somatic Na + -H + transport, but also influences neurotransmitter release (Rocha et al 2008). To analyse the effect of zoniporide on synaptic transmission, we used acute mouse brain slices.…”

“…Amiloride also inhibits several isoforms of the Na + -H + exchanger NHE1 (Masereel et al 2003), with high selectivity for the NHE1 isoform, a ubiquitously expressed membrane protein that regulates cell volume and intracellular pH. Additionally, in neurones, NHE1 influences neurotransmission by mediating H + extrusion from synaptosomes and recovery from intracellular acidification during neuronal excitability (Rocha et al 2008). Given that NHE1 is also present in myocardium, amiloride and its analogues, as well as the NHE1 selective antagonist zoniporide, are therapeutically used in humans to prevent arrhythmia and to protect against cardiac damage during ischaemia (Masereel et al 2003;Fliegel, 2009).…”