An Alternative Exon of CAPS2 Influences Catecholamine Loading into LDCVs of Chromaffin Cells

The calcium-dependent activator proteins for secretion (CAPS) are priming factorsfor synaptic and large dense-core vesicles, promoting their entry into, and stabilizing the release-ready state. A modulatory role of CAPS in catecholamineloading of vesicleshas been suggested. Though an influence of CAPS on monoamine transporterfunction and on vesicleacidification have been reported, a role of CAPS in vesicleloading is disputed. Using expression of naturally occurring splice variants of CAPS2 into chromaffin cellsfrom CAPS1/CAPS2 double-deficient mice of both sexes, we show that an alternative exonof 40 amino acids is responsible for enhanced catecholamineloading of large dense-core vesiclesin mouse chromaffin cells. The presence of this exonleads to increased activity of both vesicular monoamine transporters. Deletion of CAPS does not alter acidification of vesicles. Our results establish a splice-variant dependent modulatory effect of CAPS on catecholaminecontent in large dense-core vesicles. SIGNIFICANCE STATEMENT The calcium activator protein for secretion (CAPS) promotes and stabilizes the entry of catecholamine-containing vesiclesof the adrenal gland into a release-ready state. Expression of an alternatively-spliced exonin CAPS leads to enhanced catecholaminecontent in chromaffin granules. This exoncodes for forty amino acids with a high proline content, consistent with an unstructured loop, present in the portion of the molecule generally thought to be involved in vesiclepriming. CAPS variants containing this exonpromote 5HT uptake into CHO cells expressing either vesicular monoamine transporter. Epigenetic tuning of CAPS variants may allow modulation of endocrine adrenaline and noradrenaline release. This mechanism may extend to monoamine release in central neurons or in the enteric nervous system.