Zinc is an essential trace element that plays a pivotal role in numerous physiological processes, including immune function, antioxidant defense, cellular signaling, and growth

Cyanide (CN) is a potent, fast-acting toxicant that impacts endogenous biomolecules in the nervous system, including acid-sensing ion channels (ASICs), which play a vital role in various neurological and psychological conditions. Here, we demonstrate that CN rapidly potentiates ASIC currents in cultured mouse cortical neurons in a dose-dependent manner while causing a leftward shift in the pH dose–response curve. Notably, this potentiation was unaffected by a 30-min CN treatment or the presence of ATP in the recording pipette. Further investigations into the role of zinc revealed that TPEN, a high-affinity zinc chelator, did not enhance ASIC currents following CN pretreatment, nor did CN influence the potentiation of ASIC currents induced by TPEN. Low-affinity zinc blocked the potentiation of ASIC currents by CN. CN potentiated ASIC currents in cortical neurons from ASIC2 but not from ASIC1a knockout mice. In experiments with CHO cells expressing homomeric ASIC1a and heteromeric ASIC1a/2, CN potentiated ASIC1a currents but had no effect on homomeric ASIC1b, ASIC2a, or ASIC3 channels. Mutating lysine 133 (K133) to arginine (R) in the extracellular domain of ASIC1a abolished CN’s effect, suggesting that CN potentiates ASIC1a currents primarily via high-affinity zinc binding, with K133 being critical for this modulation.

Substance use disorders (SUDs) involve drug-evoked adaptations in reward, stress, and relapse circuits. We propose that extracellular pH fluctuations may provide an additional, context-dependent regulatory signal. Neural activity, vesicle release, respiration, metabolism, lactate/proton transport, and vascular responses can produce local acidifying or alkalinizing changes whose direction and magnitude depend on compartment and buffering. Acid-sensing ion channels (ASICs) can respond rapidly to appropriate acidic excursions, whereas proton-sensing G protein-coupled receptors (GPCRs), including GPR4 and GPR68, may encode changes in ambient proton-dependent signaling over longer timescales. ASIC studies demonstrate effects on cocaine-related plasticity and behavior; global GPR4 deletion alters cocaine-induced locomotor responses and sensitization but does not identify the responsible cell population or establish a role in reinforcement or relapse. We critically examine the uncertain sign of synaptic pH transients, GPR65 and GPR132, astrocyte–neuron metabolic coupling, and potential human measurement strategies. We propose direct pH recording combined with circuit-resolved causal perturbations to test this two-arm model without presuming that drug exposure produces uniform acidosis.