CCKAR

Official Full Name

cholecystokinin A receptor

Organism

Homo sapiens

GeneID

886

Background

This gene encodes a G-protein coupled receptor that binds non-sulfated members of the cholecystokinin (CCK) family of peptide hormones. This receptor is a major physiologic mediator of pancreatic enzyme secretion and smooth muscle contraction of the gallbladder and stomach. In the central and peripheral nervous system this receptor regulates satiety and the release of beta-endorphin and dopamine. [provided by RefSeq, Jul 2008]

Synonyms

CCK-A; CCK1R; CCKRA; CCK-1R; CCK1-R;

Bio Chemical Class

GPCR rhodopsin

Protein Sequence

MDVVDSLLVNGSNITPPCELGLENETLFCLDQPRPSKEWQPAVQILLYSLIFLLSVLGNTLVITVLIRNKRMRTVTNIFLLSLAVSDLMLCLFCMPFNLIPNLLKDFIFGSAVCKTTTYFMGTSVSVSTFNLVAISLERYGAICKPLQSRVWQTKSHALKVIAATWCLSFTIMTPYPIYSNLVPFTKNNNQTANMCRFLLPNDVMQQSWHTFLLLILFLIPGIVMMVAYGLISLELYQGIKFEASQKKSAKERKPSTTSSGKYEDSDGCYLQKTRPPRKLELRQLSTGSSSRANRIRSNSSAANLMAKKRVIRMLIVIVVLFFLCWMPIFSANAWRAYDTASAERRLSGTPISFILLLSYTSSCVNPIIYCFMNKRFRLGFMATFPCCPNPGPPGARGEVGEEEEGGTTGASLSRFSYSHMSASVPPQ

Open

Disease

Binge eating disorder, Bladder disorder, Digestive system disease, Dyspepsia, Influenza, Obesity, Pancreatic cancer, Pancreatic malfunction

Approved Drug

Clinical Trial Drug

8 +

Discontinued Drug

19 +

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Detailed Information

The cholecystokinin A receptor (CCKAR) is a G-protein-coupled receptor (GPCR) that binds to non-sulfated members of the cholecystokinin (CCK) family of peptide hormones. This receptor plays a crucial role in regulating various physiological processes, particularly within the digestive and nervous systems. Among numerous vital roles, the protein it genes for modulates satiety signals in the brain, gallbladder contraction, and pancreatic enzyme release. CCKAR is a vital participant in preserving both digestive homeostasis and neurological function as a member of the Class A/1 GPCR family, so it is a target for treatments very extensively.

Structural and Functional Overview of CCKAR

The core of CCKAR's operation is its capacity to interact with the peptide hormone cholecystokinin (CCK), involved in several digestive processes. Compared to another peptide hormone with related actions, gastrin, CCKAR has a somewhat low affinity for CCK. Primary mediated by G proteins activating the phosphatidylinositol-calcium second messenger pathway, CCK's interaction with CCKAR sets off multiple downstream signaling cascades. Different physiological effects follow from these interactions based on the tissue in which CCKAR is expressed.

Figure 1 describes the structural representation and 3D models of the CCK-8-activated CCKAR receptor coupled with different G proteins (Gq, Gs, Gi), illustrating the receptor's G-protein coupling promiscuity and the associated complexes. Figure 1. Schematic of G-protein coupling promiscuity of CCKAR. (Liu Q, et al., 2021)

Typical of GPCRs, CCKAR has seven transmembrane domains that enable ligand binding and consequent signal transmission. Cryo-electron microscopy has advanced recently to provide a structural understanding of how CCKAR interacts with many G protein subtypes, including Gs, Gi, and Gq. Fascinatingly, whereas CCKAR shows identical conformations across many complexes, the coupling specificity of the receptor is determined by small differences in the G protein "wave hook" and the intracellular loop 3 (ICL3). These results clarify the capacity of the receptor to interact with many G protein subtypes, a phenomenon known as GPCR promiscuity, therefore adding complexity to its functional repertoire.

Role of CCKAR in the Digestive System

CCKAR is essential in the digestive system for control of pancreatic enzyme production and smooth muscle contraction. Its activation by CCK causes the pancreas to produce digestive enzymes, therefore helping to break down nutrients. Furthermore, CCKAR activation in the gallbladder causes smooth muscle contraction, which helps bile to be released into the small intestine, therefore facilitating the breakdown and absorption of fat. The receptor also controls gastric motility, therefore guiding the evacuation of stomach contents into the duodenum.

The fact that CCKAR controls gastrointestinal (GI) motility and secretion emphasizes its relevance in preserving digestive homeostasis. Different digestive problems including gallbladder malfunction and reduced pancreatic output might result from disturbances in CCKAR function. Moreover, CCKAR has been implicated in conditions such as actinobacillosis and panic disorder, suggesting a broader role in maintaining overall physiological balance.

CCKAR in the Nervous System

Apart from its function in the digestive tract, CCKAR is also expressed in the central and peripheral neural systems where it affects eating behavior and neuropeptide release. CCKAR is involved in the control of satiety in the brain, hence signaling fullness after meals. CCKAR is essential for energy balance as this role is mediated by the interaction of the receptor with pathways regulating appetite.

Moreover, CCKAR has been shown to control the release of two neuropeptides engaged in reward and pain modulation: dopamine and beta-endorphin. Natural opioids like beta-endorphin help the body respond to stress and pain; dopamine is a fundamental neurotransmitter in the reward circuits of the brain. The capacity of CCKAR to control these neuropeptides relates the receptor to mood control and behavior, therefore providing possible therapy paths for illnesses like anxiety, depression, and eating problems.

Therapeutic Potential of Targeting CCKAR

CCKAR is a desirable target for treatments as it is so important in controlling digestive and brain activities. From digestive problems to neurological ailments, drugs that alter CCKAR activity might cure a variety of maladies. For pancreatitis, for instance, a CCKAR antagonist might be given to lower pancreatic enzyme output and therefore ease symptoms. Similarly, by boosting satiety signals, CCKAR agonists may help control appetite in those with obesity or eating disorders.

Targeting CCKAR could provide fresh strategies for treating anxiety, depression, and addiction in the framework of neurological diseases. The participation of the receptor in dopamine and beta-endorphin production implies that changing its activity might affect mood control and reward pathways. Furthermore, a possible target for treating metabolic diseases like diabetes and obesity is CCKAR's influence on satiety and food behavior.

References:

Wank SA. Cholecystokinin receptors. Am J Physiol. 1995;269(5 Pt 1):G628-G646. doi:10.1152/ajpgi.1995.269.5.G628
Wang HH, Portincasa P, Liu M, et al. An Update on the Lithogenic Mechanisms of Cholecystokinin a Receptor (CCKAR), an Important Gallstone Gene for Lith13. Genes (Basel). 2020 Nov 29;11(12):1438.
Nishimura S, Bilgüvar K, Ishigame K, et al. Functional synergy between cholecystokinin receptors CCKAR and CCKBR in mammalian brain development. PLoS One. 2015;10(4):e0124295.
Liu Q, Yang D, Zhuang Y, et al. Ligand recognition and G-protein coupling selectivity of cholecystokinin A receptor. Nat Chem Biol. 2021;17(12):1238-1244.

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