title: The M2 muscarinic receptors are essential for signaling in the heart left ventricle during restraint stress in mice.
abstract: We hypothesized that muscarinic receptors (MRs) in the heart have a role in stress responses and thus investigated changes in MR signaling (gene expression, number of receptors, adenylyl cyclase (AC), phospholipase C (PLC), protein kinase A and C (PKA and PKC) and nitric oxide synthase [NOS]) in the left ventricle, together with telemetric measurement of heart rate (HR) in mice (wild type [WT] and M2 knockout [KO]) during and after one (1R) or seven sessions (7R) of restraint stress (seven mice per group). Stress decreased M2 MR mRNA and cell surface MR in the left ventricle in WT mice. In KO mice, 1R, but not 7R, decreased surface MR. Similarly, AC activity was decreased in WT mice after 1R and 7R, whereas in KO mice, there was no change. PLC activity was also decreased after 1R in WT and KO mice. This is in accord with the concept that cAMP is a key player in HR regulation. No change was found with stress in NOS activity. Amount of AC and PKA protein was not changed, but was altered for PKC isoenzymes (PKCα, β, γ, η and ϵ (increased) in KO mice, and PKCι (increased) in WT mice). KO mice were more susceptible to stress as shown by inability to compensate HR during 120 min following repeated stress. The results imply that not only M2 but also M3 are involved in stress signaling and in allostasis. We conclude that for a normal stress response, the expression of M2 MR to mediate vagal responses is essential.
authors.affiliation: 1st Faculty of Medicine, Institute of Physiology, Charles University , Prague , Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Tomankova
authors.forename: Paulina
authors.initials: P
authors.lastname: Valuskova
authors.forename: Eva
authors.initials: E
authors.lastname: Varejkova
authors.forename: Jana
authors.initials: J
authors.lastname: Rotkova
authors.forename: Jan
authors.initials: J
authors.lastname: Benes
authors.forename: Jaromir
authors.initials: J
authors.lastname: Myslivecek
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015870:Gene Expression; D006321:Heart; D006339:Heart Rate / Q000235:genetics* / Q000502:physiology; D006352:Heart Ventricles / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000235:genetics*; D011976:Receptors, Muscarinic / Q000235:genetics; D012149:Restraint, Physical; D015398:Signal Transduction; D013315:Stress, Psychological / Q000235:genetics* / Q000503:physiopathology; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases
keywords: Adenylyl cyclase; heart; muscarinic receptors; phospholipase C; protein kinase C; stress