The copine protein NRA-1 regulates activity-dependent cholinergic signalling and sensory integration in C. elegans

Abstract

Membrane-associated proteins regulate the localisation and function of ligand-gated ion channels, yet how they shape synaptic efficacy and behaviour remains poorly understood. Here, we identify the copine family protein NRA-1 as an activity-dependent regulator of cholinergic signalling and sensory circuit function. Electrophysiological recordings at the neuromuscular junction of C. elegans revealed that loss of nra-1 does not alter responses to acute agonist application or the initial response to synaptic stimulation but selectively impairs sustained and repetitive cholinergic transmission during ongoing activity. Single-channel recordings further demonstrated that NRA-1 does not affect the unitary conductance of levamisole-sensitive acetylcholine receptors (L-AChRs) but instead regulates receptor gating by increasing channel closed times and reducing opening frequency, resulting in an overall decrease in receptor activity. Despite these synaptic defects, nra-1 mutants displayed normal baseline locomotion but exhibited impaired chemotaxis, abnormal food localisation and defective egg-laying behaviour. Together, our findings identify NRA-1 as an activity-dependent regulator of postsynaptic receptor function that sustains cholinergic signalling during repeated activity and links receptor dynamics to sensory behaviour. These results establish copine proteins as important modulators of synaptic efficacy and suggest that activity-dependent control of receptor function represents a conserved mechanism for tuning neural circuit performance.