Secretagogues cause ubiquitination and down-regulation of inositol 1, 4,5-trisphosphate receptors in rat pancreatic acinar cells.
BACKGROUND & AIMS: The action of several exocrine pancreas secretagogues depends on the second messenger inositol 1,4, 5-trisphosphate (IP3), which, via endoplasmic reticulum-located IP3 receptors, mobilizes intracellular Ca2+ stores. Signaling pathways like this one are regulated at multiple loci. To determine whether IP3 receptors are one of these loci, we measured IP3 receptor concentration, distribution, and modification in secretagogue-stimulated rat pancreatic acinar cells. METHODS: Isolated rat pancreatic acinar cells were exposed to cholecystokinin and other secretagogues, or rats were injected intraperitoneally with cerulein. Then samples of cells or pancreata were probed for IP3 receptor content and distribution as well as for ubiquitin association with IP3 receptors. RESULTS: Secretagogues rapidly down-regulated acinar cell IP3 receptors both in vitro and in vivo. They also elicited receptor redistribution and caused receptors to become ubiquitinated, indicating that the ubiquitin/proteasome proteolytic pathway contributes to the down-regulation. Surprisingly, however, proteasome inhibitors did not block IP3 receptor down-regulation, and phospholipase Cbeta1 and protein kinase C also were down-regulated. Thus, secretagogues simultaneously activate an additional proteolytic pathway. CONCLUSIONS: Secretagogues rapidly down-regulate IP3 receptors and other proteins involved in intracellular signaling by a mechanism that involves, but is not limited to, the ubiquitin/proteasome pathway. Loss of these proteins may account for the disruption of Ca2+ mobilization that occurs in models of acute pancreatitis, and may contribute to cell adaptation under physiological conditions.[1]References
- Secretagogues cause ubiquitination and down-regulation of inositol 1, 4,5-trisphosphate receptors in rat pancreatic acinar cells. Wojcikiewicz, R.J., Ernst, S.A., Yule, D.I. Gastroenterology (1999) [Pubmed]
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