Does mammalian heart contain only the m2 muscarinic receptor subtype?

Sharma, Virendra K.; Colecraft, Henry M.; Rubin, Lisa; Sheu, Shey‐Shing

doi:10.1016/s0024-3205(97)00043-x

Cited by 29 publications

(21 citation statements)

References 18 publications

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“…Moreover, VAChT mice presented exacerbated M 2 responses, in contrast to M 2 -AChR knockout mice, in which M 2 responses were absent (26). There is another consideration: the existence of other types of muscarinic receptors in the heart, albeit with lower levels of expression, has been reported (44,49). Indeed, we could also detect M 1 and M 3 muscarinic receptor messages in ventricular cardiomyocytes, and their expression was elevated in VAChT KD HOM mice.…”

Section: Discussionmentioning

confidence: 63%

Dysautonomia Due to Reduced Cholinergic Neurotransmission Causes Cardiac Remodeling and Heart Failure

Lara

Damasceno²,

Pires

et al. 2010

Molecular and Cellular Biology

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Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction.

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Section: Discussionmentioning

confidence: 63%

Dysautonomia Due to Reduced Cholinergic Neurotransmission Causes Cardiac Remodeling and Heart Failure

Lara

Damasceno²,

Pires

et al. 2010

Molecular and Cellular Biology

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“…For example, it has been demonstrated that mRNA for mAChR subtypes that were missed by Northern blot studies were detected by use of reverse transcription followed by polymerase chain reaction (RT-PCR) in neuroblastoma cells as well as in guinea pig ventricular myocytes (7,9). Previous work in this laboratory, employing the techniques of single-cell RT-PCR on cardiac myocytes isolated from adult rat ventricle has demonstrated the existence of m 1 mAChR mRNA in addition to m 2 mRNA (10,11). Furthermore, we have demonstrated that the activation of m 1 mAChRs leads to an increase in muscle shortening and Ca 2ϩ transients.…”

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confidence: 50%

Signaling Mechanisms Underlying Muscarinic Receptor-mediated Increase in Contraction Rate in Cultured Heart Cells

Colecraft

Egamino

Sharma

et al. 1998

Journal of Biological Chemistry

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We have investigated the mechanisms by which stimulation of cardiac muscarinic receptors result in paradoxical stimulatory effects on cardiac function, using cultured neonatal rat ventricular myocytes as a model system. Application of low concentrations of carbachol (CCh) (EC 50 Stimulation of postsynaptic muscarinic acetylcholine receptors (mAChRs)1 on cardiac cells is able to produce dual effects on the heartbeat. Classically, stimulation of the vagus nerve or the application of low concentrations of muscarinic cholinergic agonists produces characteristic negative chronotropic and inotropic effects on cardiac tissue and cells (1). Paradoxically, under appropriate conditions, activation of cardiac mAChRs elicits stimulatory effects on the rate of beating and contractile force of the heart. These latter effects often require higher concentrations of agonist and in some cardiac cell types are only seen after pretreatment with pertussis toxin (PTx) (2-4).It has been widely believed, based on both radioligand binding techniques as well as Northern blot analyses, that cardiac cells express only the m 2 mAChR subtype on their surface membranes (5-8). However, more recent findings suggest limits in the sensitivity of these techniques in detecting low levels of protein and mRNA (6). For example, it has been demonstrated that mRNA for mAChR subtypes that were missed by Northern blot studies were detected by use of reverse transcription followed by polymerase chain reaction (RT-PCR) in neuroblastoma cells as well as in guinea pig ventricular myocytes (7, 9). Previous work in this laboratory, employing the techniques of single-cell RT-PCR on cardiac myocytes isolated from adult rat ventricle has demonstrated the existence of m 1 mAChR mRNA in addition to m 2 mRNA (10, 11). Furthermore, we have demonstrated that the activation of m 1 mAChRs leads to an increase in muscle shortening and Ca 2ϩ transients. However, the signal transduction pathway mediating this stimulatory response is still unknown. Moreover, there is no report on the role of m 1 mAChRs in the regulation of heart rate.In the present studies, we have taken advantage of the ability of cultured neonatal rat ventricular myocytes to contract spontaneously and have utilized them as a cardiac cell model system to investigate the role of m 1 mAChRs in the regulation of rate of contraction. By applying a number of complementary approaches, including single-cell intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) measurements, single-cell RT-PCR, immunocytochemistry and antisense technology, four specific questions were addressed. 1) Do cultured neonatal rat ventricular myocytes exhibit dual responses to mAChR stimulation in a manner similar to that observed in other cardiac cell preparations? 2) How many subtypes of mAChRs are expressed in cultured neonatal rat ventricular myocytes? 3) Which mAChR subtype mediates the stimulatory effects of muscarinic agonists on the rate of contraction? 4) What second messenger system is involved in generating this response?A prelim...

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“…21 We found that both M 1 and M 2 muscarinic receptor mRNA was first expressed in CMG cells after 5-AZ treatment and that carbachol increased IP 3 production in a dosedependent manner, which was markedly inhibited by atropine and AFDX116. Since the localization of muscarinic receptors is tissue-specific, it does not seem surprising that these receptors were expressed when they were directed to differentiate into cardiomyocytes, in the same pattern as ␤ 1 -and ␤ 2 -adrenergic receptors.…”

Section: -And M 2 -Muscarinic Receptor Expression In Cmg Cellsmentioning

confidence: 71%

Bone Marrow–Derived Regenerated Cardiomyocytes (CMG Cells) Express Functional Adrenergic and Muscarinic Receptors

et al. 2002

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Background-We recently reported that cardiomyocytes could be differentiated from bone marrow mesenchymal stem cells in vitro by 5-azacytidine treatment. In native cardiomyocytes, adrenergic and muscarinic receptors play crucial roles in mediating heart rate, conduction velocity, contractility, and cardiac hypertrophy. We investigated whether these receptors are expressed in differentiated CMG cells, and if so, whether they have downstream signaling systems. Methods and Results-Reverse transcription-polymerase chain reaction revealed that CMG cells had already expressed ␣ 1A -, ␣ 1B -, and ␣ 1D -adrenergic receptor mRNA before 5-azacytidine treatment, whereas expression of ␤ 1 -, ␤ 2 -adrenergic and M 1 -, M 2 -muscarinic receptors was first detected at 1 day. Phenylephrine dose-dependently induced phosphorylation of ERK1/2, which was completely inhibited by prazosin, and significantly increased cell size. Isoproterenol augmented cAMP by 38-fold, which was fully inhibited by propranolol. Isoproterenol (10 Ϫ7 mol/L) increased the spontaneous beating rate by 47.6% (basal, 127Ϯ16 bpm), and propranolol and CGP20712A (␤ 1 -selective blocker) reduced it by 79.0% and 71.0%, respectively, whereas ICI118551 (␤ 2 -selective blocker) induced slight reduction. Cell motion, percent shortening, and contractile velocity were increased by 37.5%, 26.9%, and 50.6%, respectively, in response to isoproterenol. Phenylephrine and isoproterenol augmented ANP and BNP gene expressions. Carbachol increased IP 3 by 32-fold, which was markedly inhibited by atropine as well as AFDX116 (M 2 -selective blocker) measured by radioimmunoassay. Conclusions-These

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Does mammalian heart contain only the m2 muscarinic receptor subtype?

Cited by 29 publications

References 18 publications

Dysautonomia Due to Reduced Cholinergic Neurotransmission Causes Cardiac Remodeling and Heart Failure

Dysautonomia Due to Reduced Cholinergic Neurotransmission Causes Cardiac Remodeling and Heart Failure

Signaling Mechanisms Underlying Muscarinic Receptor-mediated Increase in Contraction Rate in Cultured Heart Cells

Bone Marrow–Derived Regenerated Cardiomyocytes (CMG Cells) Express Functional Adrenergic and Muscarinic Receptors

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