Acetylcholine receptors cardiac

Proska, J., and Tucek, S. (1994). Mechanisms of steric and cooperative interactions of alcuronium on cardiac muscarinic acetylcholine receptors. Mol. Pharmacol. 45 709-717. 

A G-protein-mediated effect has an absolute requirement for GTP. Reference has already been made to the requirement for GTP in reconstituting hormone-stimulated adenylate cyclase activity. A similar requirement can be demonstrated when the effector is an ion channel, such as the cardiac atrial inward-rectifier K+ channel which is activated following stimulation of the M2 muscarinic acetylcholine receptor. Thus, in the experiment illustrated in Figure 7.8, the channel recorded with a cell-... 

The cholinesterase inhibitors can increase activity in both sympathetic and parasympathetic ganglia supplying the heart and at the acetylcholine receptors on neuroeffector cells (cardiac and vascular smooth muscles) that receive cholinergic innervation. 

Recall that scopolamine, an ingredient in henbane, blocks muscarinic acetylcholine receptors. This blockade essentially removes the influence of the parasympathetic nervous system on the body. In the absence of this influence, the balance of forces is upset and the sympathetic nervous system gains the upper hand thus, your heart rate increases, your pupils dilate, salivation stops, your ability to urinate is impaired, and you become constipated overall, things get very uncomfortable. But none of this is directly lethal (unless the constipation makes one commit suicide). If you do die from an overdose of henbane, it is believed to result from either a complex series of events in your brain that lead to the loss of control of your diaphragm, causing death from asphyxiation, or from cardiac arrest. This is why the deadly nightshade is so deadly and how Shakespeare chose to kill King Hamlet with henbane. 

Acetylcholine receptors are classified as either muscarinic cholinergic receptors or nicotinic cholinergic receptors. The alkaloid muscarine mimics the effects produced by stimulation of the parasympathetic system. These effects are postganglionic and are exerted on exocrine glands, cardiac muscle, and smooth muscle. The alkaloid nicotine mimics the actions of acetylcholine, which include stimulation of all autonomic ganglia, stimulation of the adrenal medulla, and contraction of skeletal muscle. 

Neither non-activated Gj nor non-activated or GTPyS-preactivated Gs elicit K+ channel opening under these conditions. Further, addition of complexes of a-GTP S of Gk resolved from (3y subunits, but not of /3-y subunits, mimic the action of Gk on atrial membrane patch K+ channels [150], This indicates that Gk acts on K+ channels via its a subunit as does Gs acting on adenylyl cyclase and T acting on cGMP-specific PDE. Figure 3 summarizes evidence that led to identification of Gk as the link between acetylcholine receptors and cardiac muscarinic K+ channels. Figure 4 presents key experiments that show direct activation of K+ channels by Gk and its a subunit. 

The most dangerous adverse effect of muscle relaxants in the ICU is suxamethonium-induced hyperkale-mic cardiac arrest (112-117). Prolonged immobilization is believed to result in a spread of immature acetylcholine receptors on the muscle surface, which may mediate massive long-lasting potassium release if suxamethonium is given (118). By this mechanism, cardiac arrest... 

Carbamazepine is both an important anticonvulsant in therapeutic doses and a powerful proconvulsant in overdose. The therapeutic anticonvulsant mechanism is primarily related to blockade of presynaptic voltage-gated sodium channels. Blockade of the sodium channels is believed to inhibit the release of synaptic glutamate and possibly other neurotransmitters. Carbamazepine is also a powerful inhibitor of the muscurinic and nicotinic acetylcholine receptors, N-methyl-D-aspartate (NMDA) receptors and the central nervous system (CNS) adenosine receptors. In addition, carbamazepine is structurally related to the cyclic antidepressant impramine and in massive overdose may affect cardiac sodium channels. 

Feron O, Smith TW, Michel T, Kelly RA. Dynamic targeting of the agonist-stimulated m2 muscarinic acetylcholine receptor to caveolae in cardiac myocytes. J Biol Chem 1997 272 17,744-17,748. 

From these results it was concluded that there was one type of acetylcholine receptor on skeletal muscles and at nerve synapses (the nicotinic receptor), and a different sort of acetylcholine receptor on smooth muscle and cardiac muscle (the muscarinic receptor). 

Voltage and G-protein-gated channels K ch and Km (6 helices) quite similar to Ky(s) and Ky(r), but which interact with Gi proteins coupled to M2 muscarinic acetylcholine receptors, or with Gq proteins coupled to M3 receptors, respectively. Stimulation of M2 or M3 muscarinic receptors by acetylcholine in pacemaker cardiac... 

Cardiac Muscarinic Acetylcholine Receptors Activate a G Protein That Opens Channels... 

Binding of acetylcholine to nicotinic acetylcholine receptors In striated muscle cells generates an action potential that triggers muscle contraction (see Figure 7-45). In contrast, the muscarinic acetylcholine receptors In cardiac muscle are Inhibitory. Binding of acetylcholine to these receptors slows the... 

The cardiac muscarinic acetylcholine receptor is a GPCR whose effector protein is a channel. Receptor activation causes release of the subunit, which opens channels (see Figure 13-21). The resulting hyperpolarlza-tion of the cell membrane slows the rate of heart muscle contraction. 

Fig. 47.3. Events leading to sarcoplasmic reticulum calcium release in skeletal muscle. 1. Acetylcholine, released at the synaptic cleft, binds to acetylcholine receptors on the sar-colemma, leading to a change of conformation of the receptors such that they now act as an ion pore. This allows sodium to enter the cell and potassium to leave. 2. The membrane polarization that results from these ion movements is transmitted throughout the muscle fiber by the T-tubule system. 3. A receptor in the T-tubules (the dihydropyridine receptor, DHPR) is activated by membrane polarization (a voltage-gated activation) such that activated DHPR physically binds to and activates the ryanodine receptor in the sarcoplasmic reticulum (depolarization-induced calcium release). 4. The activation of the ryanodine receptor, which is a calcium channel, leads to calcium release from the SR into the sarcoplasm. In cardiac muscle, activation of DHPR leads to calcium release from the T-tubules, and this small calcium release is responsible for the activation of the cardiac ryanodine receptor (calcium-induced calcium release) to release large amounts of calcium into the sarcoplasm.

Reflex changes in heart rate involve ganglionic transmission. Activation of alphaj receptors on blood vessels by phenylephrine elicits a reflex bradycardia since mean blood pressure is increased. One of the characteristic effects of tubocurarine is its block of autonomic ganglia—this action can interfere with reflex changes in heart rate. Tubocurarine would not prevent bradycardia due to neostigmine (an inhibitor of acetylcholinesterase) since this occurs via stimulation by acetylcholine of cardiac muscarinic receptors. 

A third type of Ca wave was demonstrated in Xenopus oocytes expressing acetylcholine receptors coupled to IP3 production (Lechleiter et al., 1991). While the majority of waves were planar or concentric, the latter patterns sometimes transformed into spiral waves. Although it is difficult to judge whether the waves are of type 1 or 2 in that study, because of the subtraction of successive images, waves of type 2 are clearly seen in experiments performed on the same cells under similar conditions (Brooker et al., 1990). Spiral waves of Ca have also been observed (Lipp Niggli, 1993) in single cardiac cells. 

Hunter, D., and Nathanson, N. (1985). Assay of Muscarinic Acetylcholine Receptor Function in Cultured Cardiac Cells by Stimulation of Rb Efflux, Anal. Biochem. 149 392-398. 

Sparteine is an alkaloid that inhibits channels and Na ion flux and activates a muscarinergic acetylcholine receptor. In small doses, this alkaloid acts as a stimulant while in large doses it has a paralyzing effect on autonomic ganglia. Medical applications may include possible correction of cardiac arrhythmia. 

Elucidation of the stmctural requirements for dmg interaction at the recognition site is by the study of stmcture—activity relationships (SAR), in which, according to a specific biologic response, the effects of systematic molecular modification of a parent dmg stmcture are determined. Such studies have permitted the classification of discrete classes of pharmacological receptors. For example, the neurotransmitter acetylcholine acts at both peripheral and central receptors which are of at least three distinct types. The effects of acetylcholine are mimicked in smooth and cardiac muscles and secretory... 

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