Textbook - BIOLOGICAL CHEMISTRY - Hubskyi Y.I. - 2000

Chapter VI. BIOCHEMISTRY OF PHYSIOLOGICAL FUNCTIONS AND SPECIALIZED TISSUES

CHAPTER 33. BIOCHEMISTRY OF THE NERVOUS SYSTEM. MOLECULAR PSYCHOBIOLOGY

33.2. NEUROTRANSMITTERS. RECEPTORS FOR NEUROTRANSMITTERS AND PHYSIOLOGICALLY ACTIVE COMPOUNDS

Neurotransmitters (neuromediators) are Biomolecules that ensure the transmission of impulses (chemical signals) in The Nervous system from one neuron to another, as well as from a neuron to an effector organ.

Based on their chemical nature, neurotransmitters are classified into the following compounds (F. Hucho, 1986): acetylcholine, biogenic amines (catecholamines — norepinephrine, dopamine, serotonin), Amino Acids and their derivatives (γ-aminobutyric acid — GABA, Glycine, glutamate, aspartate), Peptides — Neuropeptides (endorphins, enkephalins, substance P, etc.). Proline, taurine, β-Alanine, adenosine, and Prostaglandins can also perform mediator Functions in the nervous system.

Neurotransmitter receptors are Membrane Proteins (mostly Glycoproteins) localized in the postsynaptic membranes of Neurons or the Plasma Membranes of effector organ Cells, which are capable of binding physiological effectors (neurotransmitters, various PACs, psychotropic compounds) and transmitting the extracellular chemical signal into the neuron.

According to the principles of their MOLECULAR Organization AND functioning, neurotransmitter receptors are predominantly ionotropic receptors (Class I receptors), i.e., those that control the opening of Ion Channels on the membrane for Ca²⁺, Na⁺, and K⁺; in this case, Components of the ion channels act as primary effectors transmitting the chemical signal to the nerve Cell (Chapter 23). In addition, the Physiological effects of certain neurotransmitters and neuromodulators (in particular, Brain neuropeptides, acetylcholine, and some biogenic amines) are mediated by metabotropic receptors (class II receptors) that activate intracellular biochemical systems through the generation of cAMP or cGMP, the activation of the phosphoinositide system, and/or an increase in the cytosolic concentration of Ca²⁺ ions. Along with neurotransmitters, numerous drugs and neurotoxins can interact with these types of receptors, acting as activators (agonists), inhibitors/blockers (antagonists), or modulators of biochemical, neurophysiological, and psychological (behavioral) effects mediated by the excitation of specific receptors in certain brain areas.

Characteristics of Individual Neurotransmitters

Acetylcholine, a derivative of Choline and acetic acid, is the most abundant neurotransmitter. Its synthesis and Cleavage occur in the cholinergic centers (structures) of the central and Peripheral Nervous System. The enzyme choline acetyltransferase is involved in the synthesis of acetylcholine:

Similar to other neurotransmitters (particularly catecholamines), the synthesis of acetylcholine takes place in nerve terminals, while its storage occurs in special synaptic vesicles. The release of the neurotransmitter into the synaptic cleft occurs As a result of neuron excitation in discrete portions ("quanta") via The Mechanism of synaptic vesicle exocytosis. The direct biochemical signal that triggers the release of acetylcholine through the presynaptic membrane is an increase in Ca²⁺ ions inside the nerve terminal. The released acetylcholine interacts with the receptor structures of the postsynaptic membrane — cholinergic receptors (ChR) (Fig. 33.1).

Fig. 33.1. Cytology/cytology/92.html">SCHEMATIC Structure OF a cholinergic synapse.

The Cleavage of the neurotransmitter in the synaptic cleft is carried out by the enzyme acetylcholinesterase (AChE).

Depending on their molecular structure, physiological and pharmacological properties, and in particular their selective sensitivity to specific Agonists and Antagonists, two main types (and several subtypes) of cholinergic receptors are distinguished:

- M-cholinergic receptors (M-ChR) — those selectively excited by the mushroom toxin muscarine;

- N-cholinergic receptors (N-ChR) — those selectively excited by the tobacco alkaloid nicotine.

M-ChRs are localized in the postsynaptic membranes of effector organ cells and in the terminal regions of parasympathetic nerve fibers. These receptors belong to the metabotropic type. The intracellular effects of their excitation are realized through an increase in the cytosolic concentration of Ca²⁺, which activates Ca²⁺-dependent guanylyl cyclase, leading to the generation of cGMP that mediates the action of M-ChR agonists on cGMP-dependent biochemical systems of respective targets.

N-ChRs are localized in the postsynaptic membranes of ganglionic cells that contact the endings of parasympathetic and sympathetic preganglionic fibers. These are receptors of the ionotropic type, The stimulation of which by acetylcholine, nicotine, and other agonists is accompanied by an increased permeability of cell membranes (of cholinergic synapses in the nervous system, Neuromuscular Junction) to Ca²⁺, Na⁺, and K⁺ ions. This effect of N-ChR activation is due to their intra-membrane organization, which is a supramolecular complex of five protein subunits (α₂, β, γ, δ) surrounding an ion channel that penetrates The Lipid Bilayer of the membrane (Fig. 33.2).

Fig. 33.2. Model of the intra-membrane ORGANIZATION OF THE N-cholinergic receptor.

Physiologically active compounds that act as AChE inhibitors are of major pharmacological and toxicological importance, causing a significant increase in neurotransmitter concentration both in Central Nervous System structures and throughout the body.

Reversible AChE inhibitors are compounds used in medical practice to enhance cholinergic impulse transmission impaired in certain neurological disorders (such as myasthenia gravis), intestinal atony, and Urinary Bladder atony. The following drugs are used for this purpose: Proserine, Physostigmine, Galantamine.

Irreversible ACh-esterase inhibitors are potent neurotoxins that trigger severe nervous system excitation accompanied by seizures and functional disorders in the cardiovascular, gastrointestinal, and other physiological systems. The most common irreversible ACh-esterase inhibitors are organophosphorus compounds (OPCs), which form a covalent bond with the Serine hydroxyl group in the enzyme's Active Site, thereby preventing its interaction with the substrate (Chapter 7).

OPCs have found extremely wide application in agriculture and households as pesticides to combat harmful insects, including chlorophos, dichlorvos, metaphos, malathion, and others. The targeted synthesis of OPCs highly toxic to warm-blooded animals led to The Development of nerve agents adopted by the military forces of many countries as chemical warfare agents (CWAs). The most well-known CWAs from the class of organophosphorus compounds include substances such as tabun, sarin, and soman.

Norepinephrine is a biogenic amine that, along with epinephrine and dopamine, belongs to the catecholamines. Unlike epinephrine, which exhibits predominantly hormonal activity, norepinephrine acts as a neurotransmitter playing a transmitter role in adrenergic synapses of the central and peripheral nervous systems.

In the human brain, noradrenergic neurons are primarily localized in the areas of the locus coeruleus, the hippocampus, and a significant portion of the Cerebral Cortex. The functional role of norepinephrine as one of the major neurotransmitters of the central nervous system is associated with maintaining the activity level of neuropsychic reactions and shaping cognitive and adaptive processes.

Adrenoceptors are widely distributed both in the nervous system and in other Organs and Tissues. There are several subtypes of adrenoceptors: α₁, α₂, β₁, and β₂, which differ in their biochemical, physiological, and pharmacological properties.

The interaction of ligands (such as norepinephrine, epinephrine, etc.) with β-adrenoceptors (β₁ and β₂) is accompanied by the activation of adenylyl cyclase, an increase in the intracellular concentration of cAMP, and—via The system of cAMP-dependent protein Kinases—the stimulation of corresponding metabolic processes and cellular physiological functions; an example of such reactions is the epinephrine-stimulated Glycogenolysis in The Liver and Muscles, and lipolysis in adipose tissue.

Unlike β-adrenoceptors, the stimulation of various α-adrenoceptor subtypes involves fundamentally different molecular mechanisms:

- stimulation of α₁-adrenoceptors increases the cytosolic concentration of Ca²⁺ ions through their transport into cells and release from internal stores, leading to the activation of Ca-dependent cellular reactions;

- stimulation of α₂-adrenoceptors through the interaction of the Ligand-receptor complex with a transducing inhibitory membrane protein (N_i) is accompanied by the inhibition of adenylyl cyclase activity and a corresponding reorganization of cGMP-dependent biochemical processes.

In the central nervous system, adrenoceptors are localized both on postsynaptic membranes (α₁-adrenoceptors), ensuring the transmission of the nerve signal to a neuron or effector organ, and on presynaptic membranes (predominantly α₂-adrenoceptors), inhibiting norepinephrine release into the synaptic cleft via negative feedback.

Norepinephrine has complex biochemical and functional connections at both pre- and postsynaptic levels with other neurotransmitters and modulators of central nervous system functions—such as acetylcholine, serotonin, dopamine, and neuropeptides.

Dopamine is a catecholamine with neurotransmitter properties that performs A number of important physiological functions in the central and peripheral nervous systems. Dopamine possesses weak sympathomimetic activity and participates in The regulation of behavior, motor function, and The activity of The Cardiovascular system, intestines, and Kidneys.

Dopamine receptors

There are several types (D₁, D₂, D₃, D₄) and subtypes of dopamine receptors that differ in their sensitivity to ligands and The Nature of the biochemical and physiological cellular responses that follow their activation.

Activation of D₁ receptors is accompanied by an increase in dopamine-sensitive adenylyl cyclase activity, followed by the engagement of the cAMP-dependent biochemical reaction cascade.

Activation of D₂ receptors leads to a decrease in adenylyl cyclase activity, intracellular calcium concentration, and the suppression of corresponding cAMP- and Ca-dependent metabolic and physiological processes.

Disruptions in dopamine METABOLISM and dopamine receptor functions are associated with the development of Schizophrenia, alcoholism, depressive states, Parkinson's disease, and other extrapyramidal disorders. The functioning of human brain dopaminergic structures is influenced by numerous psychotropic and neurotropic medications that have found wide clinical application.

Serotonin is a biogenic amine derived from Tryptophan (5-hydroxytryptamine, 5-HT). Serotonin exhibits an extremely wide spectrum of biological activity regarding the central and peripheral nervous systems, as well as other organs and tissues.

In the human central nervous system, serotonin functions as a neurotransmitter for specialized serotonergic neurons and as a modulator of other neurotransmitters' action. Serotonin receptors are divided into distinct types: 5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, and subtypes (specifically 5-HT_1A, 5-HT_1B, 5-HT_1C), which are differentiated by their sensitivity to agonists and antagonists. Serotonin receptors belong to class II (metabotropic) receptors, but differ in the Nature of the biochemical reactions accompanying their stimulation:

- excitation of 5-HT₁ receptors leads (via a GTP-binding N-protein transducer) to the activation of serotonin-sensitive Adenylyl Cyclase and an increase in cAMP levels;

- excitation of 5-HT₂ receptors is accompanied by an increase in cytosolic calcium ion concentration (due to their release from intracellular stores) and the activation of Ca-dependent biochemical processes.

The Physiological Role of serotonin in the human brain is viewed in connection with the regulation of psycho-emotional reactions such as anxiety, apprehension, aggressiveness, impulsive drives, Sexual Behavior, and the control of physiological Sleep cycles, which has led to defining serotonin as the “well-being neurotransmitter.”

Disruptions in serotonin metabolism and serotonin receptor functions affect the Pathogenesis of depressive and anxiety states, schizophrenia, alcoholism, and substance addictions. Specifically, serotonin deficiency in the brain and CEREBROSPINAL FLUID has been detected in patients with severe depression who committed suicide (H.I. Kaplan, B.J. Sadock, 1994). Ethyl alcohol preference in experimental rats depends on the function of serotonin receptors localized in the limbic system. Pharmacological agents affecting serotonergic neurotransmission, particularly 5-HT reuptake inhibitors, reduce alcohol consumption in experimental animals (W. Kostowski, 1995). Accordingly, the modulation of serotonin's PHYSIOLOGICAL AND BIOCHEMICAL effects serves as the basis for the pharmacological actions of many psychotropic and neurotropic drugs.

Amino acid neurotransmitters and their derivatives

Amino acid neurotransmitters are divided into two classes:

1) excitatory acidic amino acids;

2) inhibitory neutral amino acids.

Excitatory Amino Acids

Amino acids with neurotransmitter properties include the "excitatory amino acids" — L-glutamate and L-aspartate, whose metabolism receives significant attention in nervous system pathology, pathopsychology, and psychopharmacology. Both ionotropic and metabotropic excitatory amino acid receptors have been identified in brain cells.

Ionotropic excitatory amino acid receptors are classified into the following subclasses:

- receptors activated by glutamate and aspartate, as well as by NMDA (N-methyl-D-aspartate) — NMDA receptors;

- receptors activated by glutamate, as well as by AMPA (DL-α-amino-3-hydroxy-5-methyl-4-isoxazolonepropionic acid) and kainate — AMPA/kainate receptors.

Activation of NMDA receptors leads to an influx of extracellular calcium into The Cell through the opening of calcium channels.

Activation of AMPA/kainate receptors is accompanied by the depolarization of neuronal membranes due to the opening of Na⁺ channels; this depolarization, in turn, triggers the opening of voltage-dependent Ca²⁺ channels and an increase in intracellular Ca²⁺ concentration.

Metabotropic excitatory amino acid receptors are activated by glutamate. Activation of this receptor type, via a G-protein transducer, stimulates phosphoinositide metabolism, leading to the generation of Inositol trisphosphate and diacylglycerol — intracellular messengers that increase Ca²⁺ concentration through its mobilization from intracellular stores.

The influx of Ca²⁺ into the postsynaptic neuron resulting from the excitation of ionotropic (NMDA or AMPA/kainate) receptors induces long-term potentiation of interneuronal transmission, creating the neurophysiological foundation for learning, memory, and individual behavioral patterns.

Modulation of the excitatory amino acid receptor system plays a crucial role in understanding the Biochemical Mechanisms of action of anti-Parkinsonian, antiepileptic, and Muscle relaxant medications.

Inhibitory Amino Acids

This class of neurotransmitters includes γ-aminobutyric acid — GABA (γ-aminobutyrate; 4-aminobutyrate), glycine, taurine, and β-alanine.

GABA is the most extensively studied inhibitory neurotransmitter. By interacting with specific selective receptors (GABA receptors), this amino acid suppresses the interneuronal transmission of nerve impulses. The biochemical mechanism of GABA's inhibitory action involves the activation of Cl- ion influx across the neuronal membrane, which occurs as a result of GABA interacting with membrane chloride channels.

In accordance with these neurophysiological properties of GABA, GABA receptor agonists and compounds that potentiate GABAergic inhibitory effects exhibit anticonvulsant, tranquilizing, and sedative effects. Conversely, GABA antagonists, which reduce the inhibitory activity of GABAergic neurons (picrotoxin, bicuculline), are potent convulsants. The convulsant activity of strychnine is due to its antagonistic action on Spinal Cord glycine receptors, which are also coupled to membrane chloride channels.

Neuropeptides represent a broad class of peptide compounds synthesized primarily in Cells of the central nervous system, forming its peptidergic system and capable of significantly influencing biochemical and neurophysiological processes in the brain.

Opioid Peptides

Neuropeptides that act as endogenous ligands for brain morphine (opiate) receptors — opioid peptides — attract the greatest attention in molecular psychobiology and pharmacology. Similar to the narcotic analgesic morphine and related compounds, opioid peptides exhibit the most pronounced analgesic (pain-relieving) activity and a specific action on the human brain, which manifests as a complex psycho-emotional state of euphoria accompanied by improved mood, a sense of mental comfort, and a positive perception of the environment (D.A. Harkevich, 1993).

The main representatives of opioid neuropeptides are: Methionine (met-)-enkephalin, leucine (leu-)enkephalin, α-, β-, γ-, and δ-endorphins ("endogenous morphines"), α- and β-neoendorphins, and dynorphins A and B.

As evident from the presented primary structures, opioid neuropeptides share homologous amino acid residue sequences (positions 1-4(5) in enkephalins and endorphins, and 1-16 in all endorphins). This indicates a commonality in The structure of the genes (DNA nucleotide sequences) encoding these peptides. The direct precursor of enkephalins and endorphins is the protein proopiomelanocortin, partial Hydrolysis of which yields not only neuropeptides but also hormonal compounds such as corticotropin and β-lipotropin (Chapter 24).

Opioid Peptide Receptors

Similar to other Membrane Receptors for neurotransmitters, opiate receptors are divided into several subtypes: μ (mu) receptors, δ (delta) receptors, κ (kappa) receptors, σ (sigma) receptors, and ε (epsilon) receptors. The highest density of opiate receptors is found in the limbic System of the brain — an evolutionarily ancient structure responsible for emotional arousal and the manifestation of the euphoric and positive emotional components of action produced by both neuropeptides and morphine-class opiate narcotics.

The biochemical mechanisms underlying opiate receptor function involve The Effect of the formed ligand-receptor system on intracellular messenger metabolism — specifically cAMP and Ca²⁺ ions — which determines the direct physiological effects of a given neuropeptide.