Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer

Cancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the biological behavior of these cancers is highly dependent on bioactive molecules released by neurocrine, paracrine, and autocrine mechanisms within the tumor microenvironment. For many decades after its discovery as a neurotransmitter, acetylcholine was thought to be synthesized and released uniquely from neurons and considered the sole physiological ligand for muscarinic receptor subtypes, which were believed to have similar or redundant actions. In the intervening years, we learned this former dogma is not tenable. (1) Acetylcholine is not produced and released only by neurons. The cellular machinery required to synthesize and release acetylcholine is present in immune, cancer, and other cells, as well as in lower organisms (e.g., bacteria) that inhabit the gut. (2) Acetylcholine is not the sole physiological activator of muscarinic receptors. For example, selected bile acids can modulate muscarinic receptor function. (3) Muscarinic receptor subtypes anticipated to have overlapping functions based on similar G protein coupling and downstream signaling may have unexpectedly diverse actions. Here, we review the relevant research findings supporting these conclusions and discuss how the complexity of muscarinic receptor biology impacts health and disease, focusing on their role in the initiation and progression of gastric, pancreatic, and colon cancers.

Solifenacin-induced acute psychosis: a case report

Solifenacin is a muscarinic receptor antagonist that has been used to treat overactive bladder since 2004. It has a great affinity for the detrusor M3 receptor, which must be stimulated for bladder muscle contraction, and demonstrates the most selective profile to the bladder of the muscarinic receptor subtypes. It is thought that urinary antimuscarinic agents, due to their passage to the central nervous system and lipophilic properties, may cause central nervous system symptoms in some rare cases. A case report of a 42-year-old male patient who had an acute psychotic attack as a result of solifenacin treatment for overactive bladder is presented in this article.

Functional Characterization of Muscarinic Receptors in Human Schwann Cells

Functional characterization of muscarinic cholinergic receptors in myelinating glial cells has been well described both in central and peripheral nervous system. Rat Schwann cells (SCs) express different muscarinic receptor subtypes with the prevalence of the M2 subtype. The selective stimulation of this receptor subtype inhibits SC proliferation, improving their differentiation towards myelinating phenotype. In this work, we describe for the first time that human SCs are cholinoceptive as they express several muscarinic receptor subtypes and, as for rat SCs, M2 receptor is one of the most abundant. Human SCs, isolated from adult nerves, were cultured in vitro and stimulated with M2 muscarinic agonist arecaidine propargyl ester (APE). Similarly to that observed in rat, M2 receptor activation causes a decreased cell proliferation and promotes SC differentiation as suggested by increased Egr2 expression with an improved spindle-like shape cell morphology. Conversely, the non-selective stimulation of muscarinic receptors appears to promote cell proliferation with a reduction of SC average cell diameter. The data obtained demonstrate that human SCs are cholinoceptive and that human cultured SCs may represent an interesting tool to understand their physiology and increase the knowledge on how the cholinergic stimulation may contribute to address human SC development in normal and pathological conditions.

Effects mediated by M2 muscarinic orthosteric agonist on cell growth in human neuroblastoma cell lines

The role of muscarinic receptors has been largely documented over the past few decades. Recently we demonstrated that the activation of M2 muscarinic receptors arrested cell proliferation and induced apoptosis in glioblastoma and in other tumour types. This paper aims to evaluate the expression of the M2 muscarinic receptor subtypes in different neuroblastoma cell lines and its role in the control of cell proliferation and survival. Neuroblastoma is the most common solid extracranial tumour, appearing during childhood and displaying a differentiated clinical behaviour. Considering the high homology between muscarinic receptor subtypes, we have identified Arecaidine Propargyl Ester (APE) as a selective orthosteric agonist for M2 muscarinic receptors. Using this agonist, we demonstrate how a selective activation of the M2 receptor subtype negatively modulates cell growth without affecting cell survival in different human neuroblastoma cell lines. As similarly demonstrated in other cell types, following the M2 receptor silencing by short-interference RNA, the effects of APE are completely abolished. We conclude by confirming the ability of APE to bind selectively M2 muscarinic receptor subtypes. Moreover, for the first time we demonstrate that M2 receptor activation inhibits cell growth also in human neuroblastoma cells, indicating that M2 receptors may be an interesting therapeutic target in several solid tumours.