scholarly journals Role of Muscarinic Acetylcholine Receptors in Breast Cancer: Design of Metronomic Chemotherapy

2019 ◽  
Vol 14 (2) ◽  
pp. 91-100 ◽  
Author(s):  
María E. Sales ◽  
Alejandro J. Español ◽  
Agustina R. Salem ◽  
Paola M. Pulido ◽  
Y. Sanchez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Acetylcholine Receptors ◽  
Metronomic Chemotherapy ◽  
Chemotherapeutic Agents ◽  
Muscarinic Acetylcholine Receptors ◽  
Therapeutic Interventions ◽  
Dependent Manner ◽  
Muscarinic Agonists ◽  
Muscarinic Acetylcholine

Background: muscarinic acetylcholine receptors (mAChRs) have attracted interest as targets for therapeutic interventions in different illnesses like Alzheimer´s disease, viral infections and different tumors. Regarding the latter, many authors have studied each subtype of mAChRs, which seem to be involved in the progression of distinct types of malignancies. Methods: We carefully revised research literature focused on mAChRs expression and signaling as well as in their involvement in cancer progression and treatment. The characteristics of screened papers were described using the mentioned conceptual framework. Results: Muscarinic antagonists and agonists have been assayed for the treatment of tumors established in lung, brain and breast with beneficial effects. We described an up-regulation of mAChRs in mammary tumors and the lack of expression in non-tumorigenic breast cells and normal mammary tissues. We and others demonstrated that muscarinic agonists can trigger anti-tumor actions in a dose-dependent manner on tumors originated in different organs like brain or breast. At pharmacological concentrations, they exert similar effects to traditional chemotherapeutic agents. Metronomic chemotherapy refers to the administration of anti-cancer drugs at low doses with short intervals among them, and it is a different regimen applied in cancer treatment reducing malignant growth and angiogenesis, and very low incidence of adverse effects. Conclusion: The usage of subthreshold concentrations of muscarinic agonists combined with conventional chemotherapeutic agents could be a promising tool for breast cancer therapy.

Immunoglobulin G from Breast Cancer Patients Regulates MCF-7 Cells Migration and MMP-9 Activity by Stimulating Muscarinic Acetylcholine Receptors

2012 ◽  
Vol 33 (2) ◽  
pp. 427-435 ◽  
Author(s):  
Laura T. Pelegrina ◽  
María Gabriela Lombardi ◽  
Gabriel L. Fiszman ◽  
María E. Azar ◽  
Carlos Cresta Morgado ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Immunoglobulin G ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Breast Cancer Patients ◽  
Muscarinic Acetylcholine ◽  
Mcf 7

scholarly journals Control of Cardiac Function in vivo with a Light-Regulated Drug

2018 ◽  
Author(s):  
Fabio Riefolo ◽  
Carlo Matera ◽  
Aida Garrido-Charles ◽  
Alexandre M. J. Gomila ◽  
Luca Agnetta ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Mammalian Cells ◽  
Acetylcholine Receptors ◽  
Genetic Manipulation ◽  
Muscarinic Acetylcholine Receptors ◽  
Therapeutic Interventions ◽  
Muscarinic Acetylcholine ◽  
First Time

<p>Remote control of physiological functions with light offers the promise of unveiling their complex spatiotemporal dynamics in vivo, and enabling highly focalized therapeutic interventions with reduced systemic toxicity. Optogenetic methods have been implemented in the heart, but the need of genetic manipulation jeopardizes clinical applicability. This study aims at developing, testing and validating the first light-regulated drug with cardiac effects, in order to avoid the requirement of genetic manipulation offered by optogenetic methods. A M2 muscarinic acetylcholine receptors (mAChRs) light-regulated drug (PAI) was designed, synthesized and pharmacologically characterized. The design was based on the orthosteric mAChRs agonist Iperoxo, an allosteric M2 ligand, and a photoswitchable azobenzene linker. PAI can be reversibly photoisomerized between <i>cis</i> and <i>trans</i> configurations under ultraviolet (UV) and visible light, respectively, and it reversibly photoswitches the activity of M2 muscarinic acetylcholine receptors. We have evaluated <i>in vitro</i> photoresponses using a calcium imaging assay in genetically unmodified receptors overexpressed in mammalian cells. Furthermore, using this new chemical tool, we demonstrate for the first time photoregulation of cardiac function <i>in vivo</i> in wildtype frog tadpoles and in rats with a method that does not require genetic manipulation. Such a new approach may enable enhanced spatial and temporal selectivity for cardiovascular drugs.</p>

scholarly journals Age-Dependent Effects of Conditioning on Cholinergic and Vasopressin Systems in the Rat Suprachiasmatic Nucleus

2003 ◽  
Vol 384 (5) ◽  
pp. 729-736 ◽  
Author(s):  
B. A. M. Biemans ◽  
E. A. Van der Zee ◽  
S. Daan
Keyword(s):  
Fear Conditioning ◽  
Suprachiasmatic Nucleus ◽  
Acetylcholine Receptors ◽  
Circadian System ◽  
Muscarinic Acetylcholine Receptors ◽  
Dependent Manner ◽  
Aged Rats ◽  
Muscarinic Acetylcholine ◽  
Young Rats ◽  
Age Dependent

Abstract Active shock avoidance was used to explore the impact of behavioural stimulation on the neurochemistry of the suprachiasmatic nucleus. We have found previously that the expression of muscarinic acetylcholine receptors in the suprachiasmatic nucleus of young rats was significantly enhanced 24 hours after fear conditioning. Here, we investigated whether this observation is age-dependent. We used 26 month-old Wistar rats with a deteriorated circadian system, and compared them with young rats (4 months of age) with an intact circadian system. Vasopressin, representing a major output system of the suprachiasmatic nucleus, was studied in addition to muscarinic receptors. Young rats showed a significant increase in immunostaining for muscarinic acetylcholine receptors 24 h after training, corroborating earlier observations. Aged rats did not show such an increase. In contrast, aged rats did show an increase in vasopressin immunoreactivity 24 h after fear conditioning, both at the level of content and cell number, while young rats did not reveal a significant rise. Thus, it seems that these two neurochemical systems in the suprachiasmatic nucleus are regulated independently. The results further demonstrate that the circadian pacemaker is influenced by fear conditioning in an age-dependent manner.

Propofol-induced Depression of Cultured Rat Ventricular Myocytes Is Related to the M2-acetylcholine Receptor–NO–cGMP Signaling Pathway 

1999 ◽  
Vol 91 (6) ◽  
pp. 1712-1712 ◽  
Author(s):  
Shuji Yamamoto ◽  
Shin Kawana ◽  
Atsushi Miyamoto ◽  
Hideyo Ohshika ◽  
Akiyoshi Namiki
Keyword(s):  
Acetylcholine Receptor ◽  
Acetylcholine Receptors ◽  
Ventricular Myocytes ◽  
Receptor Activation ◽  
Muscarinic Acetylcholine Receptors ◽  
No Production ◽  
Dependent Manner ◽  
Rat Ventricular Myocytes ◽  
Muscarinic Acetylcholine ◽  
Nitrite Production

Background It is well-known that propofol sometimes causes bradycardia or asystole during anesthesia; however, the direct effect of propofol on the myocardium remains unclear. Previous reports showed the contribution of muscarinic acetylcholine receptors to propofol-induced bradycardia. Conversely, it was suggested recently that nitric oxide (NO) plays an important role in mediating the effect of vagal stimulation in the autonomic regulation of the heart. Therefore, the authors investigated the effects of propofol on spontaneous contraction and NO production in cultured rat ventricular myocytes. Methods The authors measured chronotropic responses of cultured rat ventricular myocytes induced by propofol stimulation with a sensor, a fiber-optic displacement measurement instrument. The authors also quantitatively analyzed NO metabolite production in cultured myocytes by measuring the levels of nitrite and nitrate in a high-performance liquid chromatography reaction system. The influence of propofol on muscarinic acetylcholine receptors of myocyte membranes was also measured with a competitive binding assay using [3H]quinuclidinyl benzilate ([3H]QNB). Results Propofol caused negative chronotropy in a dose-dependent manner. Propofol (IC50) also caused the enhancement of nitrite production in cultured myocytes. Eighty percent of the enhancement of nitrite production induced by propofol (IC50) stimulation was abolished by pretreatment with atropine, methoctramine, or N(G)-monomethyl-L-arginine acetate (L-NMMA). The negative chronotropy induced by propofol (IC50) stimulation was reduced to 40-50% by pretreatment with atropine, methoctramine, L-NMMA, or 1H[1,2,4]oxadiazolo[4,3-alpha]quanoxalin-1-one, a selective inhibitor of guanylyl cyclase. Propofol displaced [3H]QNB binding to the cell membrane of myocytes in a concentration-dependent manner. Conclusion These results suggest that the negative chronotropy induced by propofol is mediated in part by M2-acetylcholine receptor activation, which involves the enhancement of NO production in cultured rat ventricular myocytes.

scholarly journals Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors

2018 ◽  
Vol 150 (10) ◽  
pp. 1360-1372 ◽  
Author(s):  
Wessel A.C. Burger ◽  
Patrick M. Sexton ◽  
Arthur Christopoulos ◽  
David M. Thal
Keyword(s):  
Crystal Structures ◽  
Acetylcholine Receptors ◽  
Allosteric Modulation ◽  
Muscarinic Acetylcholine Receptors ◽  
Therapeutic Interventions ◽  
Structural Basis ◽  
Muscarinic Acetylcholine ◽  
Subtype Selectivity ◽  
Gpcr Activation ◽  
Allosteric Mechanisms

Recent breakthroughs and developments in structural biology have led to a spate of crystal structures for G protein–coupled receptors (GPCRs). This is the case for the muscarinic acetylcholine receptors (mAChRs) where inactive-state structures for four of the five subtypes and two active-state structures for one subtype are available. These mAChR crystal structures have provided new insights into receptor mechanisms, dynamics, and allosteric modulation. This is highly relevant to the mAChRs given that these receptors are an exemplar model system for the study of GPCR allostery. Allosteric mechanisms of the mAChRs are predominantly consistent with a two-state model, albeit with some notable recent exceptions. Herein, we discuss the mechanisms for positive and negative allosteric modulation at the mAChRs and compare and contrast these to evidence offered by pharmacological, biochemical, and computational approaches. This analysis provides insight into the fundamental pharmacological properties exhibited by GPCR allosteric modulators, such as enhanced subtype selectivity, probe dependence, and biased modulation while highlighting the current challenges that remain. Though complex, enhanced molecular understanding of allosteric mechanisms will have considerable influence on our understanding of GPCR activation and signaling and development of therapeutic interventions.

scholarly journals Control of Cardiac Function in vivo with a Light-Regulated Drug

2019 ◽  
Author(s):  
Fabio Riefolo ◽  
Carlo Matera ◽  
Aida Garrido-Charles ◽  
Alexandre M. J. Gomila ◽  
Luca Agnetta ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Mammalian Cells ◽  
Acetylcholine Receptors ◽  
Genetic Manipulation ◽  
Muscarinic Acetylcholine Receptors ◽  
Therapeutic Interventions ◽  
Muscarinic Acetylcholine ◽  
First Time

<p>Remote control of physiological functions with light offers the promise of unveiling their complex spatiotemporal dynamics in vivo, and enabling highly focalized therapeutic interventions with reduced systemic toxicity. Optogenetic methods have been implemented in the heart, but the need of genetic manipulation jeopardizes clinical applicability. This study aims at developing, testing and validating the first light-regulated drug with cardiac effects, in order to avoid the requirement of genetic manipulation offered by optogenetic methods. A M2 muscarinic acetylcholine receptors (mAChRs) light-regulated drug (PAI) was designed, synthesized and pharmacologically characterized. The design was based on the orthosteric mAChRs agonist Iperoxo, an allosteric M2 ligand, and a photoswitchable azobenzene linker. PAI can be reversibly photoisomerized between <i>cis</i> and <i>trans</i> configurations under ultraviolet (UV) and visible light, respectively, and it reversibly photoswitches the activity of M2 muscarinic acetylcholine receptors. We have evaluated <i>in vitro</i> photoresponses using a calcium imaging assay in genetically unmodified receptors overexpressed in mammalian cells. Furthermore, using this new chemical tool, we demonstrate for the first time photoregulation of cardiac function <i>in vivo</i> in wildtype frog tadpoles and in rats with a method that does not require genetic manipulation. Such a new approach may enable enhanced spatial and temporal selectivity for cardiovascular drugs.</p>

scholarly journals Control of Cardiac Function in vivo with a Light-Regulated Drug

2019 ◽  
Author(s):  
Fabio Riefolo ◽  
Carlo Matera ◽  
Aida Garrido-Charles ◽  
Alexandre M. J. Gomila ◽  
Luca Agnetta ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Mammalian Cells ◽  
Acetylcholine Receptors ◽  
Genetic Manipulation ◽  
Muscarinic Acetylcholine Receptors ◽  
Therapeutic Interventions ◽  
Muscarinic Acetylcholine ◽  
First Time

<p>Remote control of physiological functions with light offers the promise of unveiling their complex spatiotemporal dynamics in vivo, and enabling highly focalized therapeutic interventions with reduced systemic toxicity. Optogenetic methods have been implemented in the heart, but the need of genetic manipulation jeopardizes clinical applicability. This study aims at developing, testing and validating the first light-regulated drug with cardiac effects, in order to avoid the requirement of genetic manipulation offered by optogenetic methods. A M2 muscarinic acetylcholine receptors (mAChRs) light-regulated drug (PAI) was designed, synthesized and pharmacologically characterized. The design was based on the orthosteric mAChRs agonist Iperoxo, an allosteric M2 ligand, and a photoswitchable azobenzene linker. PAI can be reversibly photoisomerized between <i>cis</i> and <i>trans</i> configurations under ultraviolet (UV) and visible light, respectively, and it reversibly photoswitches the activity of M2 muscarinic acetylcholine receptors. We have evaluated <i>in vitro</i> photoresponses using a calcium imaging assay in genetically unmodified receptors overexpressed in mammalian cells. Furthermore, using this new chemical tool, we demonstrate for the first time photoregulation of cardiac function <i>in vivo</i> in wildtype frog tadpoles and in rats with a method that does not require genetic manipulation. Such a new approach may enable enhanced spatial and temporal selectivity for cardiovascular drugs.</p>

scholarly journals Cholinergically stimulated gastric acid secretion is mediated by M3 and M5 but not M1 muscarinic acetylcholine receptors in mice

2005 ◽  
Vol 288 (6) ◽  
pp. G1199-G1207 ◽  
Author(s):  
Takeshi Aihara ◽  
Yusuke Nakamura ◽  
Makoto M. Taketo ◽  
Minoru Matsui ◽  
Susumu Okabe
Keyword(s):  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Receptor Subtype ◽  
Gastric Fistula ◽  
Antral Mucosa ◽  
Dependent Manner ◽  
Muscarinic Acetylcholine

Muscarinic acetylcholine receptors play an important role in the regulation of gastric acid secretion stimulated by acetylcholine; nonetheless, the precise role of each receptor subtype (M1–M5) remains unclear. This study examined the involvement of M1, M3, and M5 receptors in cholinergic regulation of acid secretion using muscarinic receptor knockout (KO) mice. Gastric acid secretion was measured in both mice subjected to acute gastric fistula production under urethane anesthesia and conscious mice that had previously undergone pylorus ligation. M3 KO mice exhibited impaired gastric acid secretion in response to carbachol. Unexpectedly, M1 KO mice exhibited normal intragastric pH, serum gastrin and mucosal histamine levels, and gastric acid secretion stimulatied by carbachol, histamine, and gastrin. Pirenzepine, known as an M1-receptor antagonist, inhibited carbachol-stimulated gastric acid secretion in a dose-dependent manner in M1 KO mice as well as in wild-type (WT) mice, suggesting that the inhibitory effect of pirenzepine on gastric acid secretion is independent of M1-receptor antagonism. Notably, M5 KO mice exhibited both significantly lower carbachol-stimulated gastric acid secretion and histamine-secretory responses to carbachol compared with WT mice. RT-PCR analysis revealed M5-mRNA expression in the stomach, but not in either the fundic or antral mucosa. Consequently, cholinergic stimulation of gastric acid secretion is clearly mediated by M3 (on parietal cells) and M5 receptors (conceivably in the submucosal plexus), but not M1 receptors.

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