| First Author | Brockhaus J | Year | 2018 |
| Journal | J Neurosci | Volume | 38 |
| Issue | 38 | Pages | 8277-8294 |
| PubMed ID | 30104341 | Mgi Jnum | J:266683 |
| Mgi Id | MGI:6200131 | Doi | 10.1523/JNEUROSCI.0511-18.2018 |
| Citation | Brockhaus J, et al. (2018) alpha-Neurexins Together with alpha2delta-1 Auxiliary Subunits Regulate Ca(2+) Influx through Cav2.1 Channels. J Neurosci 38(38):8277-8294 |
| abstractText | Action potential-evoked neurotransmitter release is impaired in knock-out neurons lacking synaptic cell-adhesion molecules alpha-neurexins (alphaNrxns), the extracellularly longer variants of the three vertebrate Nrxn genes. Ca(2+) influx through presynaptic high-voltage gated calcium channels like the ubiquitous P/Q-type (CaV2.1) triggers release of fusion-ready vesicles at many boutons. alpha2delta Auxiliary subunits regulate trafficking and kinetic properties of CaV2.1 pore-forming subunits but it has remained unclear if this involves alphaNrxns. Using live cell imaging with Ca(2+) indicators, we report here that the total presynaptic Ca(2+) influx in primary hippocampal neurons of alphaNrxn triple knock-out mice of both sexes is reduced and involved lower CaV2.1-mediated transients. This defect is accompanied by lower vesicle release, reduced synaptic abundance of CaV2.1 pore-forming subunits, and elevated surface mobility of alpha2delta-1 on axons. Overexpression of Nrxn1alpha in alphaNrxn triple knock-out neurons is sufficient to restore normal presynaptic Ca(2+) influx and synaptic vesicle release. Moreover, coexpression of Nrxn1alpha together with alpha2delta-1 subunits facilitates Ca(2+) influx further but causes little augmentation together with a different subunit, alpha2delta-3, suggesting remarkable specificity. Expression of defined recombinant CaV2.1 channels in heterologous cells validates and extends the findings from neurons. Whole-cell patch-clamp recordings show that Nrxn1alpha in combination with alpha2delta-1, but not with alpha2delta-3, facilitates Ca(2+) currents of recombinant CaV2.1 without altering channel kinetics. These results suggest that presynaptic Nrxn1alpha acts as a positive regulator of Ca(2+) influx through CaV2.1 channels containing alpha2delta-1 subunits. We propose that this regulation represents an important way for neurons to adjust synaptic strength.SIGNIFICANCE STATEMENT Synaptic transmission between neurons depends on the fusion of neurotransmitter-filled vesicles with the presynaptic membrane, which subsequently activates postsynaptic receptors. Influx of calcium ions into the presynaptic terminal is the key step to trigger vesicle release and involves different subtypes of voltage-gated calcium channels. We study the regulation of calcium channels by neurexins, a family of synaptic cell-adhesion molecules that are essential for many synapse properties. Using optical measurements of calcium influx in cultured neurons and electrophysiological recordings of calcium currents from recombinant channels, we show that a major neurexin variant facilitates calcium influx through P/Q-type channels by interacting with their alpha2delta-1 auxiliary subunits. These results propose a novel way how neurons can modulate the strength of distinct synapses. |
