Neurexins cluster Ca ²⁺ channels within the presynaptic active zone

Abstract

To achieve ultrafast neurotransmission, neurons assemble synapses with highly organized presynaptic and postsynaptic nanomachines that are aligned by synaptic adhesion molecules. How functional assembly of presynaptic active zones is controlled via trans‐synaptic interactions remains unknown. Here, we conditionally deleted all three neurexin adhesion molecules from presynaptic neurons of the calyx of Held in the mouse auditory system, a model synapse that allows precise biophysical analyses of synaptic properties. The pan‐neurexin deletion had no effect on synapse development or the basic release machinery, but dramatically impaired fast neurotransmitter release. The overall properties of presynaptic calcium ion channels appeared normal, as reflected by the similar characteristics of calcium currents recorded at the nerve terminals. However, the pan‐neurexin deletion significantly impaired the tight coupling of calcium influx to exocytosis, thereby suppressing neurotransmitter release. Furthermore, the pan‐neurexin deletion reduced the function of calcium‐activated BK potassium channels, whose activation depends on their tight association with presynaptic calcium channels. Together, these results suggest that neurexins perform a major function at the calyx synapse in coupling presynaptic calcium channels to release sites.

Compartment-Specific Neurexin Nanodomains Orchestrate Tripartite Synapse Assembly

“…By virtue of their transsynaptic interactions, neurexins specify diverse synaptic properties. For example, neurexins regulate presynaptic Ca 2+ channels (Chen et al, 2017;Luo et al, 2020;Missler et al, 2003), postsynaptic tonic endocannabinoid synthesis (Anderson et al, 2015), and postsynaptic AMPA-(AMPARs) and NMDA-receptors (NMDARs) (Aoto et al, 2013;Dai et al, 2019).…”

UNC-2 CaV2 channel localization at presynaptic active zones depends on UNC-10/RIM and SYD-2/Liprin-α inCaenorhabditis elegans

“…One intriguing question is why UNC-10 and SYD-2 were not identified in prior C. elegans genetic studies with an integrated transgene overexpressing GFP-tagged UNC-2 (Saheki and Bargmann, 2009; Kushibiki et al, 2019). Presynaptic CaV2 channels are known to interact with several active zone proteins via direct and indirect interactions (Hibino et al, 2002; Fouquet et al, 2009; Kaeser et al, 2011; Kiyonaka et al, 2012; Tong et al, 2017; Luo et al, 2020). We speculate that in the absence of UNC-10 or SYD-2, the residual overexpressed UNC-2 at presynaptic active zones due to the weaker redundant interactions with other active zone proteins shown here, may not allow a detectable reduction in signal, while endogenously tagged UNC-2 does.…”

Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins

“…These phenotypes were entirely different from those of conventional and conditional GluD2 or Cbln1 KO mice [12][13][14][15][16] . Recent studies of four different types of synapses in conditional Nrxn TKO mice, i.e., CF-PC synapse, synapses formed by parvalbumin-or somatostatin-positive interneurons on pyramidal layer 5 neurons in the medial prefrontal cortex, and the calyx of Held synapse, reported defects in synapse-specific functions, ranging from a decrease in synaptic density to impairments of synaptic transmission and action-potential-induced Ca 2+ influx 8,9 . Intriguingly, the effect of the deletion of all NRXNs in CGCs was strikingly different from those effects.…”

“…Genetic manipulations of Nrxn genes in mice have shown that α-NRNXs and β-NRXNs play different roles in synaptic functions in different types of synapses [4][5][6][7] . Triple deletion of Nrxn1, Nrxn2, and Nrxn3 in four different types of synapses, i.e., climbing fiber (CF)-Purkinje cell (PC) synapses, synapses formed by parvalbumin-or somatostatin-positive interneurons on pyramidal layer 5 neurons of the medial prefrontal cortex, and the calyx of Held synapse, yields severe but distinct synaptic phenotypes, ranging from impairments in their distribution and functions to decreases in synapse number 8,9 .…”