Co-expression of four muscarinic receptor genes by the intrinsic neurons of the rat and guinea-pig heart

Hassall, C. J. S.; Stanford, S Clare; Burnstock, Geoffrey; Buckley, Noel J.

doi:10.1016/0306-4522(93)90149-a

Cited by 45 publications

(30 citation statements)

References 19 publications

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“…This leads to the assumption that the M 1 mRNA is located in neurons, not in cardiomyocytes. Such an assumption agrees with reports that, through in situ hybridization, M 1 mRNA could be detected in cardiac intrinsic ganglia but not in atrial myocytes or ventricular muscle (Hassall et al, 1993;Hoover et al, 1994), and with functional data concerning the M 1 receptors in autonomic ganglia (Caulfield, 1993). However, the assumption is at variance with the report that, by the use of single-cell RT-PCR, the M 1 mRNA could be detected in cultured ventricular myocytes (Colecraft et al, 1998).…”

Section: Discussionsupporting

confidence: 90%

“…Cellular location of the M 5 mRNA in the heart is unknown. Hassall et al (1993) could not detect the M 5 mRNA in intrinsic cardiac ganglia using in situ hybridization. Reports on the presence of M 5 mRNA in rat arteries (Phillips et al, 1997), human brain microvascular endothelial cells (Elhusseiny et al, 1999), and human skin fibroblasts (Buchli et al, 1999) suggest that cardiac endothelial cells and fibroblasts should be considered among potential sources of the M 5 mRNA we detected in the heart.…”

Section: Discussionmentioning

confidence: 82%

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Quantitation of mRNAs for M₁to M₅Subtypes of Muscarinic Receptors in Rat Heart and Brain Cortex

Krejčı́

Tuček

2002

Mol Pharmacol

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It has been generally accepted that, of the five subtypes of muscarinic receptors (M 1 -M 5 ), only the M 2 subtype is expressed in mammalian heart. This notion has recently been challenged by a series of reports indicating that mRNAs for some or all non-M 2 subtypes are also present in mammalian heart, in parallel with the M 2 mRNA. However, the quantities of relevant mRNAs reported to be present in the heart are not known, which makes it difficult to evaluate their likely significance. We measured the concentrations of the five muscarinic mRNAs by competitive reverse transcription-polymerase chain reaction and discovered that the M 2 mRNA represents more than 90% of total muscarinic mRNAs in rat atria and in either ventricle. The concentrations of total muscarinic mRNAs and of the M 2 mRNA were more than twice as high in the atria than in the ventricles. mRNAs for all non-M 2 muscarinic receptor subtypes were also detected but represented less than 1% (M 1 and M 4 ), less than 3% (M 3 ), and less than 5% (M 5 ) of total muscarinic RNAs in the atria and ventricles. The findings support the concept of the prevalent role of the M 2 muscarinic receptors in the cholinergic control of the heart. When the same method of quantitation was applied to rat cerebral cortex, mRNAs for individual subtypes were found to represent 36% (M 1 ), 21% (M 2 ), 25% (M 3 ), 11% (M 4 ), and 7% (M 5 ) of total muscarinic mRNAs.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 82%

Quantitation of mRNAs for M₁to M₅Subtypes of Muscarinic Receptors in Rat Heart and Brain Cortex

Krejčı́

Tuček

2002

Mol Pharmacol

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“…Alternatively, because M 3 receptor-mediated positive inotropic effects were abolished by treatment with 1% Triton X-100 or indomethacin, it has been proposed that M 3 receptors present on the endocardial endothelium stimulate the production of endogenous prostaglandins eliciting positive inotropic actions (Tanaka et al, 2001). Hassall et al (1993) reported the expression of M 1 to M 4 receptor mRNA in intrinsic neurons of rat and guinea pig hearts. In the present study, we demonstrated that indomethacin inhibited the positive inotropic actions of carbachol in atria from pertussis toxin-treated mice, in agreement with a previous report (Tanaka et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

M3 Muscarinic Receptors Mediate Positive Inotropic Responses in Mouse Atria: A Study with Muscarinic Receptor Knockout Mice

Kitazawa¹,

Asakawa²,

Nakamura³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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The potential functional roles of M 3 muscarinic receptors in mouse atria were examined by pharmacological and molecular biological techniques, using wild-type mice, muscarinic M 2 or M 3 receptor single knockout (M 2 KO, M 3 KO), and M 2 and M 3 muscarinic receptor double knockout mice (M 2 /M 3 KO). Realtime quantitative reverse transcriptase-polymerase chain reaction analysis showed that the M 2 receptor mRNA was expressed predominantly in mouse atria but that the M 1 , M 3 , M 4 , and M 5 receptor subtypes were also expressed at low levels. Carbachol (10 nM-30 M) decreased the spontaneous beating frequency of right atria isolated from wild-type mice. Studies with subtype-preferring antagonists and atria from M 2 KO mice confirmed that this activity is mediated by the M 2 receptor subtype. In left atria from wild-type mice, carbachol decreased the amplitude of electrical field stimulation-evoked contractions (negative inotropic action), but this inhibition was transient and was followed by a gradual increase in contraction amplitude (positive inotropic response). In atria from M 3 KO mice, the transient negative inotropic action of carbachol changed to a sustained negative inotropic action. In contrast, in atria from M 2 KO mice, carbachol showed only positive inotropic activity. In atria from M 2 /M 3 double KO mice, carbachol was devoid of any inotropic activity. These observations, complemented by functional studies with subtype-preferring antagonists, convincingly demonstrate that atrial M 3 muscarinic receptors mediate positive inotropic effects in mouse atria. Physiologically, this activity may serve to dampen the inhibitory effects of M 2 receptor activation on atrial contractility.Muscarinic receptor stimulation by acetylcholine plays an important role in parasympathetic control of cardiac functions such as heart rate (chronotropic action), conduction velocity (dromotropic action), and contractility (inotropic action). Muscarinic receptors are prototypic members of the superfamily of G protein-coupled receptors, and molecular cloning studies have demonstrated the existence of five distinct mammalian muscarinic receptor subtypes (M 1 -M 5 ) (Caulfield and Birdsall, 1998). Based on their differential G protein-coupling properties, the five receptors can be subdivided into two major functional classes. The M 1 , M 3 , and M 5 receptors preferentially couple to G q/11 proteins, whereas the M 2 and M 4 receptors are selectively linked to G i/o proteins (Caulfield and Birdsall, 1998;Lanzafame et al., 2003). It is well documented that the heart predominantly expresses the M 2 receptor subtype (Brodde and Michel, 1999;Dhein et al., 2001). After activation of cardiac M 2 receptors, the activated ␣ subunit of G i proteins inhibits adenylate cyclase activity, resulting in a decrease of cytoplasmic cAMP, whereas the ␤␥ subunit of the G i proteins directly activates the inwardly rectifying muscarinic K ϩ channel (Yamada et al., 1998;Dhein et al., 2001). However, the M 2 receptor is not the only muscarinic ...

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“…In contrast, stimulation of M2 and M4 receptors activate G proteins, which in turn produce cAMP stimulating the activation of protein kinase A (PKA) and phosphorylation of PKA-dependent enzymes. Expression of mRNAs encoding for M1-M4 receptor subtypes has been detected in intracardiac neurons in vitro and in situ (Hassall et al 1993: Hoover et al 1994. The G-protein-coupled M2 receptor increases the K ϩ conductance in mammalian intracardiac neurons (Allen and Burnstock 1990;Xi-Moy et al 1993), whereas M4 receptor activation inhibits the voltage-dependent N-and L-type Ca 2ϩ channels .…”

Section: Introductionmentioning

confidence: 99%

Muscarinic and Nicotinic ACh Receptor Activation Differentially Mobilize Ca²⁺in Rat Intracardiac Ganglion Neurons

Beker

Weber

Fink

et al. 2003

Journal of Neurophysiology

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. Muscarinic and nicotinic ACh receptor activation differentially mobilize Ca 2ϩ in rat intracardiac ganglion neurons. J Neurophysiol 90: 1956-1964, 2003. First published May 21, 2003 10.1152/jn.01079.2002. The origin of intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) transients stimulated by nicotinic (nAChR) and muscarinic (mAChR) receptor activation was investigated in fura-2-loaded neonatal rat intracardiac neurons. ACh evoked [Ca 2ϩ ] i increases that were reduced to ϳ60% of control in the presence of either atropine (1 M) or mecamylamine (3 M) and to Ͻ20% in the presence of both antagonists. Removal of external Ca 2ϩ reduced ACh-induced responses to 58% of control, which was unchanged in the presence of mecamylamine but reduced to 5% of control by atropine. The nAChR-induced [Ca 2ϩ ] i response was reduced to 50% by 10 M ryanodine, whereas the mAChRinduced response was unaffected by ryanodine, suggesting that Ca 2ϩ release from ryanodine-sensitive Ca 2ϩ stores may only contribute to the nAChR-induced [Ca 2ϩ ] i responses. Perforated-patch whole cell recording at -60 mV shows that the rise in [Ca 2ϩ ] i is concomitant with slow outward currents on mAChR activation and with rapid inward currents after nAChR activation. In conclusion, different signaling pathways mediate the rise in [Ca 2ϩ ] i and membrane currents evoked by ACh binding to nicotinic and muscarinic receptors in rat intracardiac neurons.

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Co-expression of four muscarinic receptor genes by the intrinsic neurons of the rat and guinea-pig heart

Cited by 45 publications

References 19 publications

Quantitation of mRNAs for M₁to M₅Subtypes of Muscarinic Receptors in Rat Heart and Brain Cortex

Quantitation of mRNAs for M₁to M₅Subtypes of Muscarinic Receptors in Rat Heart and Brain Cortex

M3 Muscarinic Receptors Mediate Positive Inotropic Responses in Mouse Atria: A Study with Muscarinic Receptor Knockout Mice

Muscarinic and Nicotinic ACh Receptor Activation Differentially Mobilize Ca²⁺in Rat Intracardiac Ganglion Neurons

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Co-expression of four muscarinic receptor genes by the intrinsic neurons of the rat and guinea-pig heart

Cited by 45 publications

References 19 publications

Quantitation of mRNAs for M1to M5Subtypes of Muscarinic Receptors in Rat Heart and Brain Cortex

Quantitation of mRNAs for M1to M5Subtypes of Muscarinic Receptors in Rat Heart and Brain Cortex

M3 Muscarinic Receptors Mediate Positive Inotropic Responses in Mouse Atria: A Study with Muscarinic Receptor Knockout Mice

Muscarinic and Nicotinic ACh Receptor Activation Differentially Mobilize Ca2+in Rat Intracardiac Ganglion Neurons

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Quantitation of mRNAs for M₁to M₅Subtypes of Muscarinic Receptors in Rat Heart and Brain Cortex

Quantitation of mRNAs for M₁to M₅Subtypes of Muscarinic Receptors in Rat Heart and Brain Cortex

Muscarinic and Nicotinic ACh Receptor Activation Differentially Mobilize Ca²⁺in Rat Intracardiac Ganglion Neurons