Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer
Abstract
:1. Introduction
2. Muscarinic Receptor Ligands
2.1. Overview
2.2. Neuronal and Non-Neuronal Acetylcholine
2.3. Bile Acids as Physiological Bioactive Muscarinic Receptor Ligands
3. Muscarinic Receptor Subtypes, Signaling, and Anatomic and Cellular Distribution
3.1. Overview
3.2. CHRM1/M1R
3.3. CHRM2/M2R
3.4. CHRM3/M3R
3.5. CHRM4/M4R
3.6. CHRM5/M5R
4. Differential Role of Muscarinic Receptor Subtype Activation in GI Cancers
4.1. Overview
4.2. Gastric Adenocarcinoma
4.3. Pancreatic Adenocarcinoma
4.4. Colon Adenocarcinoma
4.5. Role of Muscarinic Receptor Activation within the Enteric Nervous System in GI Neoplasia
5. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Sources of Acetylcholine | Refs. | |
---|---|---|
Neurons | ||
Autonomic nervous system | Preganglionic sympathetic/parasympathetic neurons | [23] |
Peripheral nervous system | Terminal ends of axons at neuromuscular junctions | [23] |
Central nervous system | Primarily interneurons | [23,24] |
Non-Neuronal Cells | ||
Immunocytes | CD4 + T cells; B cells; NK cells | [25,26,27] |
Placental trophoblast | [28] | |
Keratinocytes | [29] | |
Cardiomyocytes | [30] | |
Airway epithelial cells | [31] | |
Vascular endothelial cells | [32] | |
Urothelial cells | [33,34] | |
Cancer cells | Colon, stomach, lung, and others | [12,35,36] |
MR Subtype (Gene) | G-Protein | Ligands | Tissue Distribution | Physiological Actions | Actions in GI Cancers | Refs. |
---|---|---|---|---|---|---|
M1R (CHRM1) | Gq/11 | ACh, BA, cholesterol (allosteric) | Brain, gastric mucosa, respiratory epithelium, skin, melanocytes, immunocytes | Mediates gastric pepsinogen secretion | Protects against PDAC and colon neoplasia | [34,40,41,50,51,52,53] |
M2R (CHRM2) | Gi/o | ACh | Brain, heart, ENS, gastric mucosa, skin, bladder, melanocytes, smooth muscle, immunocytes | Modulates cardiac rhythm, GI motility | None reported | [34,50,53,54,55,56] |
M3R (CHRM3) | Gq/11 | ACh, BA | Gastric chief and parietal cells, colon epithelial cells, smooth muscle, ENS, brain, skin, melanocytes, immunocytes | Mediates gastric acid and pepsinogen secretion; GI motility | Promotes gastric and colon cancer cell proliferation and PDAC severity | [37,38,50,52,57,58,59,60,61,62] |
M4R (CHRM4) | Gi/o | ACh | Brain, gastric mucosa, small intestine, skin, melanocytes, immunocytes | Enhances gastric acid secretion; regulates striatal dopamine release | None reported | [34,50,57,63,64] |
M5R (CHRM5) | Gq/11 | ACh | Brain, cerebral vasculature, ENS; mRNA expressed in testes, placenta, thyroid, small intestine, immunocytes | Enhances gastric acid secretion; regulates striatal dopamine release; mediates SNc excitability | None reported | [34,50,53,61,63,65,66] |
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Schledwitz, A.; Sundel, M.H.; Alizadeh, M.; Hu, S.; Xie, G.; Raufman, J.-P. Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer. Int. J. Mol. Sci. 2021, 22, 13153. https://doi.org/10.3390/ijms222313153
Schledwitz A, Sundel MH, Alizadeh M, Hu S, Xie G, Raufman J-P. Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer. International Journal of Molecular Sciences. 2021; 22(23):13153. https://doi.org/10.3390/ijms222313153
Chicago/Turabian StyleSchledwitz, Alyssa, Margaret H. Sundel, Madeline Alizadeh, Shien Hu, Guofeng Xie, and Jean-Pierre Raufman. 2021. "Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer" International Journal of Molecular Sciences 22, no. 23: 13153. https://doi.org/10.3390/ijms222313153