CADPS

CADPS/CAPS (UNC-31 in C. elegans) is a Ca2+-regulated cytosolic factor that is selectively required for the exocytosis of dense-core vesicles (DCVs), and not small clear synaptic vesicles, in neural and endocrine cells (PMID:9289490, PMID:9697858, PMID:17553987). Originally purified as a 145-kDa protein that reconstitutes the Ca2+-triggering step of DCV fusion in permeable PC12 cells and binds Ca2+ with moderate affinity (PMID:9289490), it associates peripherally with membranes, localizing specifically to plasma membranes and DCVs through high-affinity phospholipid binding, where it is essential for Ca2+-activated catecholamine and neuropeptide release (PMID:9697858). Mechanistically, CADPS acts at the docking and priming steps: in C. elegans neurons UNC-31 is required for DCV docking at the plasma membrane and for UNC-13-mediated augmentation of DCV exocytosis, and its docking defect is rescued by PKA activation (PMID:18031683). Its C2, PH, and DCV-binding domains are each required for Ca2+-evoked secretion, docking, and tethering, consistent with sequential roles in vesicle tethering, docking, and SNARE complex initiation (PMID:20515653). Functionally, DCV release through UNC-31 acts upstream of neuronal Gαs signaling near synaptic active zones to control locomotion (PMID:16272411), and through a parallel pathway controls neuropeptide-regulated fat metabolism (PMID:36302635). In humans, CADPS variants that reduce protein abundance and impair neuronal exocytosis, synaptic plasticity, and vesicular catecholamine uptake are linked to bipolar disorder, and heterozygous Cadps+/- mice display lithium-responsive manic-like behavior and stress hypersensitivity (PMID:35169262).

1. 1997 High

   Established that a dedicated cytosolic factor is required for the Ca2+-triggering step of dense-core vesicle fusion, defining CAPS as a Ca2+-regulated exocytosis factor rather than a generic cytosolic component.

   Evidence Protein purification and in vitro exocytosis reconstitution with recombinant protein substitution in permeable PC12 cells, plus direct Ca2+ binding measurement

   PMID:9289490

   Open questions at the time

   • Did not resolve which domain mediates Ca2+ binding
   • No structural mechanism for how Ca2+ binding triggers fusion
2. 1998 High

   Resolved where CAPS acts by showing it is a peripheral membrane protein selectively associated with DCVs and plasma membrane via phospholipid binding, and functionally required for neural DCV exocytosis.

   Evidence Subcellular fractionation, phospholipid binding assays, and antibody inhibition of norepinephrine release from synaptosomes

   PMID:9697858

   Open questions at the time

   • Phospholipid species/domain specificity not defined
   • No direct demonstration of the molecular step blocked by antibody
3. 2003 Low

   Identified the human CADPS C2 domain and neural/endocrine-restricted expression, supporting a calcium-sensor role in regulated exocytosis.

   Evidence Full-length cDNA cloning, computational domain analysis, and tissue expression profiling

   PMID:12659812

   Open questions at the time

   • No functional validation of the C2 domain in this study
   • Domain function inferred computationally only
4. 2004 Medium

   Placed UNC-31 in a genetic network for neurosecretory vesicle release by demonstrating a specific interaction with the IA-2 homolog CeIA-2 in the same DCV release process.

   Evidence Genetic interaction analysis with null alleles of ida-1 and unc-31 in C. elegans

   PMID:15044551

   Open questions at the time

   • No physical interaction demonstrated
   • Molecular role of CeIA-2 in the release step unresolved
5. 2005 Medium

   Connected DCV exocytosis to downstream signaling by showing UNC-31 acts upstream of neuronal Gαs near active zones to regulate locomotion, distinct from the Gαq pathway.

   Evidence Genetic epistasis, cell-specific promoter rescue, and immunostaining for UNC-31 localization in C. elegans

   PMID:16272411

   Open questions at the time

   • Identity of the released signal activating Gαs not defined
   • Single-lab epistasis
6. 2007 High

   Demonstrated the pathway specificity and step of action: UNC-31 is dedicated to DCV exocytosis and docking but dispensable for synaptic vesicle recycling, opposite to UNC-13.

   Evidence In vivo peptide release assay, FM4-64 dye uptake, cultured C. elegans neuron assays, electrophysiology, TIRF single-DCV imaging, and PKA rescue

   PMID:17553987 PMID:18031683

   Open questions at the time

   • Biochemical relationship between UNC-31 docking and UNC-13 augmentation not resolved
   • Mechanism by which PKA bypasses the docking defect unknown
7. 2010 Medium

   Assigned distinct functions to UNC-31 domains, showing C2, PH, and DCV-binding domains are each required for evoked secretion, docking, and tethering while the MUN/UNC-13 homology domain is partially dispensable.

   Evidence Domain deletion mutant rescue in unc-31 null C. elegans with locomotion, NMJ, neuropeptide release, capacitance, and docking readouts

   PMID:20515653

   Open questions at the time

   • Direct binding partners of each domain not mapped
   • Temporal ordering of tethering/docking/SNARE steps inferred, not directly measured
8. 2022 Medium

   Defined the temporal and spatial requirement for CADPS in vivo and extended its role to neuropeptide-regulated physiology, including fat metabolism via specific sensory neurons.

   Evidence Endogenous tagging, auxin-inducible degradation, live imaging, and behavioral/physiological assays in C. elegans

   PMID:36302635

   Open questions at the time

   • Identity of the BAG-neuron neuropeptide controlling fat storage not established
   • Single-lab study
9. 2022 Medium

   Linked CADPS dysfunction to human bipolar disorder by showing patient variants impair exocytosis, synaptic plasticity, and catecholamine uptake, with a lithium-responsive manic phenotype in heterozygous mice.

   Evidence Patient mutation screening, functional exocytosis/uptake assays, and Cadps+/- mouse behavioral analysis with lithium rescue

   PMID:35169262

   Open questions at the time

   • Causal mechanism linking reduced CADPS to manic behavior unresolved
   • Single-lab study without independent cohort replication
10. 2024 Medium

    Revealed homeostatic and neuropeptide-dependent consequences of UNC-31 loss at the NMJ, including postsynaptic CaV1/EGL-19 upregulation and a requirement for specific neuropeptides in cAMP-driven transmitter output.

    Evidence NMJ electrophysiology, Ca2+ imaging, expression profiling, and genetic analysis of neuropeptide and convertase mutants in C. elegans (preprint)

    Open questions at the time

    • Preprint not yet peer-reviewed
    • Mechanism coupling neuropeptide loss to failed cAMP-driven scaling unclear
11. 2025 Low

    Identified a compensatory octopamine-Gαq pathway that bypasses UNC-31 loss, with fasting and egl-30 gain-of-function rescuing locomotion defects.

    Evidence Forward genetic screen, transcriptomics, octopamine pharmacology, and egl-30 gain-of-function epistasis in unc-31 null C. elegans (preprint)

    Open questions at the time

    • Preprint, no biochemical mechanism established
    • Single lab, genetic/pharmacological epistasis only

• The structural basis by which CADPS couples Ca2+ and phospholipid binding to SNARE-dependent DCV docking and priming, and the direct molecular partners of its C2/PH/DCV-binding domains, remain unresolved.
• No structural model of CADPS on the vesicle/plasma membrane
• Direct SNARE-machinery interactions not biochemically mapped in human protein
• Mechanistic link between exocytosis defect and neuropsychiatric phenotype unestablished