Sites Of Muscarinic And Nicotinic Action Of Acetylcholine Summary Pdf

sites of muscarinic and nicotinic action of acetylcholine summary pdf

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Submitted for publication November 17,

Muscarinic acetylcholine receptor

Submitted for publication November 17, Accepted for publication September 26, Address reprint requests to Dr. Address electronic mail to: med2p virginia.

During the last decade, major advances have been made in our understanding of the physiology and pharmacology of CNS muscarinic signaling. It is time to emphasize that the well-known peripheral parasympathetic and cardiovascular actions represent only one component of muscarinic signaling. Interestingly, many new findings have the potential to influence the practice of anesthesiology.

Inhibition of muscarinic signaling may explain some of the anesthetic state, and subtype-selective drugs may allow wider perioperative manipulation of CNS muscarinic systems.

The next years will doubtlessly see progress in this area, and our specialty may well reap the benefits. IN Dale described the existence of nicotinic and muscarinic components of the cholinergic system. Cholinesterase was discovered in , [2] its name was coined in , [3] and once inhibitors of the enzyme were developed to reverse neuromuscular blockade, anesthesiologists had to deal with their muscarinic side effects. During the next 40 yr, no major breakthroughs for anesthetic practice took place in muscarinic pharmacology.

Studies performed during the past decades, however, have greatly expanded our understanding of cholinergic signaling. The development of the patch clamp [4] and single channel recording, [5] purification and reconstitution experiments, [6] and finally the molecular cloning of both nicotinic [7] and muscarinic [8] acetylcholine receptors in Numa's laboratory have provided a relatively complete picture of these receptors.

We now know that, although acetylcholine is the physiologic agonist for both, the nicotinic and muscarinic receptors are completely different entities: the first a multi-subunit, ligand-gated ion channel i. Five muscarinic receptor subtypes have now been cloned, allowing development of specific antibodies, detailed mapping of tissue distribution, and synthesis of improved subtype-specific agonists and antagonists.

It has become evident that muscarinic signaling plays an important role in the central nervous system CNS , and that anesthetics interfere significantly with this system. This article focuses on these findings. After a brief summary of the pharmacology and molecular biology of muscarinic receptors, the major functions of the CNS muscarinic systems, the interactions of anesthetics with these systems, and some clinical implications are described.

A glossary of possibly unfamiliar terms is provided at the end of the text. Until the molecular cloning of the first muscarinic receptor in , investigators depended on pharmacologic tools, primarily selective antagonists, to define the several subtypes of this receptor family. Unfortunately, none of the known antagonists are completely selective, so that subtypes had to be defined by measuring the binding properties of several compounds. Thus, equilibrium binding studies with pirenzipine initially indicated the existence of two classes of cerebral muscarinic receptors, named M1 and M2.

Kinetic studies allowed differentiation of three subtypes, [10,11] and with the development of novel antagonists this number was expanded to four M1-M4 [12] : Table 1 indicates the relative selectivity of the commonly used muscarinic antagonists, and relates the pharmacologically defined types to the cloned receptor genes. An excellent recent review of this subject is available.

The first muscarinic receptor the m1 subtype was cloned in Not only have the main classes of muscarinic receptor subtypes been cloned, but detailed information on their structure-activity relationship is available, which will prove useful in the development of new, highly selective agonist and antagonist drugs. When the DNA encoding the muscarinic receptor was isolated, it was compared to already cloned sequences, and its closest relative was found to be the visual pigment rhodopsin.

In both cases, a guanosine trisphosphate GTP -binding protein G protein transduces a ligand-induced conformational change in the membrane receptor to intracellular signaling systems. Details of G protein function and their relevance to anesthesia were reviewed recently [14,15] and will not be discussed here in detail. Several hundred receptors have now been shown to belong to the G-protein-coupled receptor superfamily, of which the muscarinic receptors form a small but important cluster.

G-protein-coupled receptors all show the same molecular pattern in their amino acid sequence: most are approximately amino acids in length and include seven hydrophobic domains of approximately 20 amino acids each.

These domains are thought to form alpha-helices traversing the membrane, leading to the designation of these proteins as seven-transmembrane, serpentine, or heptahelical receptors Figure 1. The presence of seven transmembrane segments so well predicts that the protein is a G-protein-coupled receptor that a number of "orphan" clones cloned DNA to which no function has been assigned are presumptively classified as G-protein-coupled receptors on this basis only.

Figure 1. Model of a muscarinic acetylcholine receptor. A Linear model. The whole molecule is approximately amino acids long. Seven hydrophobic stretches of approximately 20 amino acids are present, presumably forming alpha-helices that pass through the cell membrane, thus forming seven transmembrane domains t1-t7. Extracellularly the aminoterminus N and three outside loops o1 through o3 are found; intracellularly there are similarly three loops i1 through i3 , and the carboxyterminus C.

B Top-down view. Although in A the molecule is pictured as a linear complex, the transmembrane domains are thought to be in close proximity, forming an ellipse with a central ligand-binding cavity indicated by a dashed circle.

Asp and Tyr refer to two amino acids important for ligand interaction. G protein binding takes place at the i3 loop and the carboxyterminus. The G proteins stimulated consist of a large family of related heterotrimeric proteins.

They control a number of intracellular systems. Examples relevant for muscarinic signaling are G i , G o , and G q. Cloning studies have shown that most of these "subtypes" actually are subfamilies of closely related proteins, with the total number of members as yet undetermined.

G i inhibits adenylate cyclase, resulting in decreased cyclic adenosine monophosphate cAMP levels. In addition, G proteins can activate ion channels, either through a direct interaction with the channel e. Once the DNA sequence of one muscarinic receptor was known [8] other subtypes were isolated in rapid succession. Even in evolutionary distant animals like insects, muscarinic receptors are easily identified and, in fact, play important roles.

The five subtypes fall into two groups, the "odd" m1, m3, m5 and the "even" m2, m4 , based on sequence homology and second messenger signaling. Although the clones were numbered simply in the order they were identified, the m1 clone happens to show most of the properties of the pharmacologic M1 type, and the m2 clone those of the M2 type. The cloned muscarinic receptor subtypes and other members of the superfamily have been used to determine the intramolecular sites involved in ligand binding and G protein coupling.

As there is a high degree of similarity between subtypes, with of the approximately amino acids invariant, [21] specificity of ligand binding and G protein coupling must depend on relatively small changes in structure. In agreement with their functional grouping, the odd and even receptors show particularly high within-group similarities. Studies of bacteriorhodopsin a related molecule for which a three-dimensional structure has been established and adrenergic receptors have demonstrated that ligand binding takes place in a pocket, primarily consisting of the second, third, and seventh transmembrane regions t2, t3, and t7, respectively , [23,24] whereas the i3 loop and the carboxyterminus C are involved in G protein binding [25—27] and regulation through phosphorylation.

Thus, the functional domains of these receptors are well established. In the brain, with its primary function of electrical signaling, and in other organs such as the heart, muscarinic systems also transduce their actions through changes in membrane potential. Several ion conductances have been shown to be affected by muscarinic stimulation, and the effects are most easily classified as depolarizing stimulatory or hyperpolarizing inhibitory. Such is indeed seen in transfected cells, [43] but it has not been observed in neurons.

The mediator involved has not been defined. Inhibitory effects of muscarinic signaling are found in many neurons, and the best-defined pathway is by muscarinic effects on voltage-activated Calcium currents I Ca. This appears mediated by m2 or m4 receptors activating G o G proteins. Another inhibitory effect of muscarinic signaling relevant to anesthesiologists is the activation of cardiac inwardly rectifying Potassiumm channels K ir through M2 stimulation.

This is responsible for the cardiac side effects of anticholinergic drugs, and has been shown to result from direct activity of stimulated G i proteins on the channel. Figure 2 summarizes the intracellular pathways involved in muscarinic signaling.

This area is the subject of active investigation, and several recent, more extensive reviews are available. Figure 2.

Intracellular signaling by muscarinic receptors. A composite illustration of the intracellular signaling pathways employed by muscarinic receptors. A Signaling through a receptor of the "odd" group. The receptor indicated by a stylized 7-transmembrane model is activated by acetylcholine ACh and stimulates two main classes of G protein G. However, in neurons, I K Ca is often inhibited by muscarinic stimulation via unclear pathways.

B Signaling through a receptor of the "even" group. Again several G proteins are involved. Another G protein, probably G o , inhibits an N-type Calcium channel Ca through an unidentified intermediary. In cardiac tissue and possibly in neurons , activation of G K directly opens a K ir channel.

Specific types of G proteins have not been indicated in the figure, as most have not been formally identified in studies. Not all cells expressing muscarinic receptors will show all signaling pathways indicated. The cloning and subsequent study of the muscarinic receptors have provided a framework on which to base studies of interactions with anesthetics. It should now be possible to map the anesthetic interference with muscarinic functioning, described later, to a specific domain within the receptor or G protein, using standard molecular biology techniques such as the construction of chimeric receptors and site-directed mutagenesis.

These techniques allow selective modification of the amino acid structure of proteins, so that domains thought to be relevant for anesthetic interactions can either be altered or exchanged with a corresponding domain from a related protein not sensitive to anesthetics. The role of such a domain, and even of specific amino acids within the domain, in anesthetic action can thus be defined. Although the techniques are subject to a number of caveats the major one being that amino acid modification can change the conformation of a protein in unpredictable ways and with unpredictable functional results , they are potentially very powerful tools for determining the intramolecular site s of action of anesthetics.

This information would not only advance our understanding of anesthetic-muscarinic interactions, but would make the muscarinic family a model for anesthetic-protein interactions in general. The prominent role in memory and consciousness played by the CNS cholinergic system is evident from the effects of the muscarinic antagonist scopolamine. Correlating these clinical findings with a neuronal substrate has proved more difficult.

However, advances achieved using a variety of investigational techniques intracranial drug administration, in vivo microdialysis, intracellular recording, chemical neuroanatomy, and molecular biology have expanded our understanding of CNS muscarinic pathways and their roles considerably. Excellent summaries can be found in several recent texts. Figure 3 shows a simplified scheme of our current understanding of the cholinergic projection systems. The brain stem group projects rostrally along a dorsal pathway to nuclei in the thalamus and the pontine reticular formation, [62] and along a ventral pathway to the basal forebrain.

Figure 3. Schematic diagram of central nervous system muscarinic signaling systems. Muscarinic neurons are localized primarily in two groups of nuclei. The brain stem group consists of the laterodorsal tegmental nucleus ldt and the pedunculopontine tegmental nucleus ppt , and sends projections to the basal forebrain as well as the thalamus thal and hypothalamus hyp.

The forebrain group consists of the medial septum ms , the diagonal band of Broca dbb , and the nucleus basalis of Meynert nbm. Projections from these areas are to the neocortex and hippocampus hip.

Immunohistochemistry of cholinergic receptors

If your institution subscribes to this resource, and you don't have a MyAccess Profile, please contact your library's reference desk for information on how to gain access to this resource from off-campus. Please consult the latest official manual style if you have any questions regarding the format accuracy. Abbreviations ACh: acetylcholine. AChE: acetylcholinesterase. COPD: chronic obstructive pulmonary disease. HCN: hyperpolarization-activated, cyclic nucleotide-gated channels. I f : cardiac pacemaker current.

Cellular, Synaptic and Network Effects of Acetylcholine in the Neocortex

Acetylcholine ACh is known to regulate cortical activity during different behavioral states, for example, wakefulness and attention. Acetylcholine ACh has been shown to play a major role in memory processing, arousal, attention, and sensory signaling Jones ; Hasselmo ; Herrero et al. It has been demonstrated that the ACh concentration in the cerebrospinal fluid CSF increases during wakefulness and sustained attention from approximately 1 to 1. In the neocortex, release of ACh occurs predominately via afferents originating from cholinergic neurons in the nucleus basalis of Meynert of the basal forebrain Mesulam et al.

The neocortex is densely innervated by basal forebrain BF cholinergic neurons. Long-range axons of cholinergic neurons regulate higher-order cognitive function and dysfunction in the neocortex by releasing acetylcholine ACh. ACh release dynamically reconfigures neocortical microcircuitry through differential spatiotemporal actions on cell-types and their synaptic connections. At the cellular level, ACh release controls neuronal excitability and firing rate, by hyperpolarizing or depolarizing target neurons. At the synaptic level, ACh impacts transmission dynamics not only by altering the presynaptic probability of release, but also the magnitude of the postsynaptic response.

It results from the accumulation of excessive levels of acetylcholine in the synapses, glands, smooth muscles, and motor end plates where cholinergic receptors are found. Thus, the pathology of the cholinergic toxidrome and the clinical picture that results can best be understood with knowledge of the types of acetylcholine receptors, where they are located, and what physiological processes they modulate.

Cellular, Synaptic and Network Effects of Acetylcholine in the Neocortex

Muscarinic acetylcholine receptors , or mAChRs , are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons [1] and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system. Muscarinic receptors are so named because they are more sensitive to muscarine than to nicotine.

Acetylcholine and its receptors are involved in a variety of important signal transduction processes. As shown here paradigmatically for the human neuromuscular junction and the cerebral cortex, acetylcholine receptors can be visualized immunohistochemically at the cellular and subcellular level under physiological and pathological conditions. At normal motor endplates nicotinic cholinoceptors are localized at the surface of the postsynaptic junctional folds. In myasthenic syndromes investigation of muscle biopsies enables the diagnosis of receptor deficiencies at the ultrastructural level. In normal cerebral cortex pyramidal neurons are equipped with both nicotinic and muscarinic acetylcholine receptors localized to postsynaptic densities. In neuropsychiatric diseases cholinoceptor expression can be monitored at the cellular level by quantititative assessment of immunolabeled cortical neurons. This is a preview of subscription content, access via your institution.

Jack C. Waymire, Ph. Acetylcholine, the first neurotransmitter discovered, was originally described as "vagus stuff" by Otto Loewi because of its ability to mimic the electrical stimulation of the vagus nerve. It is now known to be a neurotransmitter at all autonomic ganglia, at many autonomically innervated organs, at the neuromuscular junction, and at many synapses in the CNS. Figure

ABBREVIATIONS

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