GABAA receptors mediate rapid inhibitory signalling in the central nervous system, and mutations in various subunits of these pentameric receptors are associated with epilepsy. Receptors composed of α and β subunits are highly sensitive to inhibition by extracellular Zn2+ ions; however incorporation of a γ subunit disrupts two of three known Zn2+ binding sites and greatly reduces Zn2+ sensitivity. Here we demonstrate that the epilepsy associated γ2(R43Q) mutation greatly increases the susceptibility of heterologously expressed receptors to Zn2+ inhibition while preserving functional characteristics underpinned by presence of the γ2 subunit. α1β2γ2 receptors are believed to contain a single N-terminal Zn2+ binding site. Mutation of residues contributed to this site by the α subunit ameliorated the effect of γ2(R43Q) on Zn2+ sensitivity, indicating that γ2(R43Q) allosterically affects Zn2+ binding or affects signal transduction, rather than directly interacting with Zn2+. This assertion was bolstered by the increased Zn2+ sensitivity of mutations predicted, by molecular modelling, to interact with γ2(R43Q). We also examined other epilepsy-associated γ2 mutations, γ2(K289M) and γ2(R139G), and found that they did not substantially increase sensitivity to Zn2+ inhibition. Increased Zn2+ sensitivity may be physiologically important in hippocampal neurones, where synaptic Zn2+ reaches high enough levels to modulate GABAergic signalling, and may represent a novel mechanism underlying the increased occurrence of febrile seizures reported in patients harbouring the γ2(R43Q) mutation.