Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor - PubMed (original) (raw)

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Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor

Erin E Cawston et al. Br J Pharmacol. 2010 Mar.

Abstract

Cholecystokinin (CCK) is a physiologically important gastrointestinal and neuronal peptide hormone, with roles in stimulating gallbladder contraction, pancreatic secretion, gastrointestinal motility and satiety. CCK exerts its effects via interactions with two structurally related class I guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs), the CCK(1) receptor and the CCK(2) receptor. Here, we focus on the CCK(1) receptor, with particular relevance to the broad spectrum of signalling initiated by activation with the natural full agonist peptide ligand, CCK. Distinct ligand-binding pockets have been defined for the natural peptide ligand and for some non-peptidyl small molecule ligands. While many CCK(1) receptor ligands have been developed and have had their pharmacology well described, their clinical potential has not yet been fully explored. The case is built for the potential importance of developing more selective partial agonists and allosteric modulators of this receptor that could have important roles in the treatment of common clinical syndromes.

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Figure 1

Figure 1

Schematic depiction of the signalling pathways stimulated by cholecystokinin (CCK) activation of the CCK1 receptor. CCK1 receptor activation by CCK is known to result in activation of Gq-initiated pathways with stimulation of classical second messengers (bold line) such as phospholipase C (PLC)/phosphatidylinositol 4,5-bisphosphate (PIP2)/diacylglycerol (DAG) and protein kinase C (PKC)/inositol 3, 4, 5-triphosphate (IP3) resulting in the release of intracellular calcium. Additionally, nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPr) pathways have also been implicated in the release of calcium after ligand stimulation of the receptor. A number of other signalling pathways have been shown to be activated by ligand stimulation of the CCK1 receptor. These include the class I phosphatidylinositol 3-kinase (PI3K) pathway involving Akt and stimulation of mammalian Target of Rapamycin (mTOR) that results in downstream activation of transcriptions factors, the NF-κB pathway as well as the Gs-initiated adenylate cyclase (AC) pathway. Three mitogen-activated protein kinase (MAPK) pathways have been shown to be stimulated by CCK1 receptor activation, p38-MAPK, extracellular-regulated kinase (ERK) and c-Jun amino-terminal kinase (JNK). The activation of the CCK1 receptor has also been shown to stimulate the phosphorylation of epidermal growth factor receptor (EGFR), resulting in activation of Ras that in turn has been shown to be important in the activation of the JNK and ERK pathways. While no direct evidence has shown CCK activation of arrestin family proteins, these are known to have various signalling roles in many GPCRs and bind and potentially regulate several subsets of proteins from various signalling pathways (dashed lines).

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