Command Palette

Search for a command to run...

Preprint WatchMildAugust 1st, 2026

Gastrin releasing peptide and cholecystokinin employ different intracellular pathways to elicit similar safe Ca2+ signals

Salih, M.; Gerasimenko, J. V.; Gerasimenko, O. V.; Petersen, O. H.

Gastrin releasing peptide requires CD38, the enzyme that synthesises cyclic ADP ribose and NAADP, to elicit physiological calcium spikes in pancreatic acinar cells, and acetylcholine evoked signals are partially CD38 dependent.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

Claidex records one CD38 failure, the GEN3014 HexaBody programme in relapsed or refractory multiple myeloma closed in a portfolio shutdown (gen3014-hexabody-cd38-rrmm-portfolio-shutdown). Therapeutic development against CD38 has treated the protein largely as a surface antigen for depleting antibodies. This preprint restates CD38 as a functional ectoenzyme required for physiological calcium signalling in exocrine pancreas, where loss of the enzymatic arm would be expected to alter secretagogue responses rather than simply remove a cell population. The relevance to a myeloma antibody is indirect, and the work is in pancreatic acinar cells rather than in patients, so this is recorded as a mechanistic note on off-tumour CD38 function rather than as evidence against the antigen.

Abstract excerpt

Repetitive cytosolic Ca2+ spikes in pancreatic acinar cells, elicited by low (physiological) concentrations of acetylcholine (ACh), cholecystokinin (CCK) and gastrin releasing peptide (GRP), control secretion of digestive enzymes, whereas high-intensity stimulation induces sustained Ca2+ elevation initiating acute pancreatitis. Since inositol trisphosphate (IP3) was discovered as an intracellular Ca2+ releasing messenger, it has been assumed that a major class of G-protein coupled receptors relies on this pathway. We have now compared the mechanisms of action of the three physiological stimulants, all acting on different receptors, but each coupled to the IP3 pathway. Low concentrations of CCK and GRP cannot elicit Ca2+ signals without co-operation of an additional intracellular mechanism. CCK-elicited Ca2+ signalling requires activation of intracellular receptors for nicotinic acid adenine dinucleotide phosphate (NAADP), whereas this is not the case for the action of GRP that nevertheless relies on the operation of CD38, the enzyme involved in the synthesis of both cyclic ADP ribose and NAADP. Even Ca2+ signals elicited by ACh are partially dependent on CD38. It is engagement of these additional non-IP3 pathways that allows low concentrations of secretagogues to elicit safe Ca2+ spiking and therefore secretion, obviating the need for potentially toxic high levels of secretagogues.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.