GABA and glutamate receptors belonging to the ligand-gated chloride-channel family are primary targets of insecticides and antiparasitics, so their molecular structure, pharmacology and biophysical properties have attracted significant attention. However, little is known about the physiological roles of these channels or how they regulate neuronal excitability and animal behavior. Mechanosensory neurons of VS-3 slit sensilla in the patella of the tropical wandering spider, Cupiennius salei, react to the GABAA-receptor agonists, GABA and muscimol, with depolarization and an increase in intracellular [Ca2+] and, during random noise stimulation, with a mixed inhibitory–excitatory response. We established that the GABAA-receptors in all VS-3 neurons are identical, but there are at least two types of glutamate receptors and some neurons do not respond to glutamate at all. Immunohistochemistry with antibodies against Drosophila inhibitory glutamate receptor (GluCls) α-subunit suggests that in addition to VS-3 neurons, these receptors may also be present in the efferent neurons surrounding the sensory neurons. Most VS-3 neurons were inhibited but not depolarized by glutamate during random stimulation, but some depolarized and had a similar excitatory–inhibitory response to glutamate as to muscimol. The membrane-permeable Ca2+-chelator BAPTA-AM abolished muscimol effects but potentiated glutamate effects, indicating that GABA and glutamate receptors are differentially modulated by Ca2+, leading to diverse regulation of neuronal excitability. We hypothesize that this could be achieved by different Ca2+-triggered phosphorylation processes at each receptor type. These findings are important for understanding the significance of Ca2+-mediated regulation of transmitter receptor molecules and its role in controlling excitability.