[Muscarinic modulation of cardiac activity].
The goal of the present review is to report information concerning cardiac innervation or more precisely to approach the modulation of cardiac electrical and mechanical activity by parasympathetic innervation. Acetylcholine (ACh) release by nerve endings from the vagus nerve hyperpolarizes the membrane, shortens action potential (AP) duration and has a negative inotropic effect on cardiac muscle. Toxins are usefull tools in the study of membrane signals. The Caribbean ciguatoxin (C-CTX-1) has a muscarinic effect on frog atrial fibres. The toxin evokes the release of ACh from motoneuron nerve terminals innervating this tissue which allows us to propose a model, similar to the one of the neuromuscular junction (nmj), to describe the events occurring during the triggering and release of ACh. Trachynilysin (TLY) is a proteic toxin which causes an influx of Ca2+ into the cells and releases ACh from nmj synaptic vesicles. TLY has a muscarinic effect on atrial fibres which is explicated in the release of neurotransmitter from the nerve endings generated by the TLY-induced Ca2+ influx. It is known that ACh release from nmj is known to be due to exocytosis of synaptic vesicles via the activation of a proteic complex blocked by botulinum toxins. One of these proteins SNAP-25 is the target of type A botulinum toxin (BoNT/A). The study of hearts isolated from BoNT/A poisoned frogs show that atrial AP is lengthened and reveals the presence of SNAP-25 in nerve endings of this tissue. Moreover, the electrical activity of ventricular muscle is markedly altered; in BoNT/A treated frog, an important outward current activated by internal Ca2+ develops. ACh released from nerve terminals binds to a G protein coupled membrane receptor and activates a K+ channel and other effectors. Five subtypes of muscarinic receptors have been cloned from different tissue (M1, M2, M3, M4) subtypes have been identified in cardiac tissues throughout many species. These receptors coupled with different G-proteins activate different effectors. M1 receptors modulate the cardiac plateau and therefore the magnitude of the peak contraction. M2 receptors are mainly involved in the repolarization phase of the AP and modulate the duration of the peak contraction. The roles of M3 and M4 are not yet clearly defined; however, they may activate K+ currents. In conclusion, ACh releases from parasympathetic nerve endings which innervate cardiac cells follows to similar events (Ca2+ influx; presence of a SNAP-25 protein) to those which produce ACh release from nmj, stimulates different G proteins coupled muscarinic receptors, and activates different effectors involved in the modulation of cardiac electrical and mechanical activity.
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Laboratoire d'Optique Appliquée, Unité INSERM 451, Ecole Polytechnique-ENSTA, Palaiseau, France.
D000109:Acetylcholine / Q000502:physiology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002799:Cholinergic Fibers / Q000187:drug effects / Q000502:physiology; D002922:Ciguatoxins / Q000494:pharmacology; D004285:Dogs; D005397:Fish Venoms / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins; D008959:Models, Neurological; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D011898:Ranidae; D051381:Rats; D011976:Receptors, Muscarinic / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology*
D005397:Fish Venoms; D007473:Ion Channels; D008565:Membrane Proteins; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D009419:Nerve Tissue Proteins; D011976:Receptors, Muscarinic; C494208:SNAP25 protein, human; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; C103845:trachynilysin; D002922:Ciguatoxins; D019274:Botulinum Toxins, Type A; D019204:GTP-Binding Proteins; D000109:Acetylcholine