An alternative exon of CAPS2 influences catecholamine loading into LDCVs of chromaffin cells.

The calcium-dependent activator proteins for secretion (CAPS) are priming factors for synaptic and large dense-core vesicles, promoting their entry into, and stabilizing the release-ready state. A modulatory role of CAPS in catecholamine loading of vesicles has been suggested. Though an influence of CAPS on monoamine transporter function and on vesicle acidification have been reported, a role of CAPS in vesicle loading is disputed. Using expression of naturally occurring splice variants of CAPS2 into chromaffin cells from CAPS1/CAPS2 double-deficient mice of both sexes, we show that an alternative exon of 40 amino acids is responsible for enhanced catecholamine loading of large dense-core vesicles in mouse chromaffin cells. The presence of this exon leads 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 catecholamine content in large dense-core vesicles. SIGNIFICANCE STATEMENT The calcium activator protein for secretion (CAPS) promotes and stabilizes the entry of catecholamine-containing vesicles of the adrenal gland into a release-ready state. Expression of an alternatively-spliced exon in CAPS leads to enhanced catecholamine content in chromaffin granules. This exon codes 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 vesicle priming. CAPS variants containing this exon promote 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.