NEUROTRANSMITTERS.pdf

SYNAPTIC TRANSMISSION AND NEUROTRANSMITTERS SYNAPSE Definition of Terms  Electrical signals must pass across the specialized gap region between two apposing cell membranes that is called a synapse.  The process underlying this cell-to-cell transfer of electrical sig...

SYNAPTIC TRANSMISSION AND NEUROTRANSMITTERS SYNAPSE Definition of Terms  Electrical signals must pass across the specialized gap region between two apposing cell membranes that is called a synapse.  The process underlying this cell-to-cell transfer of electrical signals is termed synaptic transmission.  Electrical synapses provide direct electrical continuity between cells by means of gap junction  chemical synapses link two cells together by a chemical neurotransmitter that is released from one cell and diffuses to another.  The interface between the motor neuron and the muscle cell is called the neuromuscular junction.  Properties of electrical and chemical synapse ELECTRICAL CHEMICAL IONOTROPIC METABOTROPIC AGONIST NONE e.g. ACh e.g. ACh MEMBRANE Connexon Receptor/channel Receptor/G PROTEIN protein SPEED OF Instantaneous 1 ms delay Seconds to minutes TRANSMISSION  Electrical synapse True structural connection formed by connexon channels of gap junctions that link the cytoplasm of two cells These channels thus provide a low-resistance path for electronic current flow and allow voltage signals to flow with little attenuation and no delay between two or more coupled cells.  Electrical Synapses Instantaneous signal transmission because current passes directly from one cell to another The presynaptic terminal must be big enough for its membrane to contain many ion channels and the postsynaptic cell must be small. to generate a large current The change in potential of the postsynaptic cell is directly related to the size and shape of the change in potential of the presynaptic cell. Electrotonic transmission Most electrical synapses can transmit both depolarizing and hyperpolarizing currents Signal transmission is similar to the passive propagation of subthreshold electrical signals along axons Rectifying synapses Gap junctions that have voltage-dependent gates that permit them to conduct depolarizing current in only one direction  Electrical Synapses Gap-junction channel Specialized region of contact between two neurons at an electrical synapse Consists of a pair of connexons (hemichannels)- one in the pre- and the other in the postsynaptic cell membrane Form a continuous bridge that provides a direct communication path between the two cells Each connexon is composed of six identical subunits called connexins. Each subunit has an N- and C-terminus with four interposed alpha-helixes. Modulatory factors: that control their opening and closing Cytoplasmic pH, Ca2+, released neurotransmitters  Electrical Synapses Role of Gap Junctions in Glial Function Astrocytes in the brain are connected to each other through gap junctions forming a glial cell network Gap junctions also enhance communication in the Schwann cells in the PNS. These gap junctions may help to hold the layers of myelin together and promote the passage of small metabolites and ions across the many layers of myelin. Glial Gap Junction Genetic Diseases Charcot-Marie-Tooth demyelinating disorder caused by single disease, mutations in a connexin gene (connexin 32) expressed in the Schwann cell that blocks gap-junction X-linked form channel function Congenital deafness Inherited mutations that prevent the function of a connexin expressed in the cochlea (connexin 26) forms gap-junction channels that are important for fluid secretion in the inner ear Chemical synapse Process of chemical transmission  Step 1: Neurotransmitter molecules are packaged into synaptic vesicles. Specific transport proteins in the vesicle membrane use the energy of an H+ gradient to energize uptake of the neurotransmitter in the vesicle.  Step 2: An action potential, which involves voltage-gated Na+ and K+ channels, arrives at the presynaptic nerve terminal Process of chemical transmission  Step 3: Depolarization opens voltage-gated Ca2+ channels, which allows Ca2+ to enter the presynaptic terminal.  Step 4: The increase in intracellular Ca2+ concentration ([Ca2+]i) triggers the fusion of synaptic vesicles with the presynaptic membrane. As a result, packets (quanta) of transmitter molecules are released into the synaptic cleft.  Step 5: The transmitter molecules diffuse across the synaptic cleft and bind to specific receptors on the membrane of the postsynaptic cell.  Process of chemical transmission  Step 6: The binding of transmitter activates the receptor, which in turn activates the postsynaptic cell.  Step 7: The process is terminated by  (1) enzymatic destruction of the transmitter  (e.g., hydrolysis of ACh by acetylcholinesterase),  (2) uptake of transmitter into the presynaptic nerve terminal or into other cells by Na+-dependent transport systems, or  (3) diffusion of the transmitter molecules away from the synapse.  Chemical Synapses Same transmitter substance can be released differently from different cells. Conventional transmitter, modulator, neurohormone The action of a transmitter depends on the properties of the postsynaptic receptors that recognize and bind the transmitter. ACh can excite some postsynaptic cells and inhibit others, and at still other cells it can produce both excitation and inhibition. Therefore, it is the receptor that determines the action of ACh, including whether a cholinergic synapse is excitatory or inhibitory. Two biochemical features common to all receptors for chemical transmitters: They are membrane-spanning proteins. The region exposed to the external environment of the cell recognizes and binds the transmitter from the presynaptic cell. They carry out an effector function within the target cell. The receptors typically influence the opening or closing of ion channels.  Chemical Synapses Functions of ionotropic and metabotropic receptors Ionotropic Receptors Metabotropic Receptors - produce relatively fast synaptic - produce slower synaptic actions actions lasting only milliseconds lasting seconds to minutes - commonly found at synapses in - act as crucial reinforcing neural circuits that mediate rapid pathways in the process behaviors, such as the stretch learning receptor reflex Ionotropic Receptor (NMJ skeletal muscle)  Ach-activated ion channel/Nicotinic AchR  Activation of ionotropic receptor → rapid opening of ion channels (Na,K)→depolarization/hyperpolarization of postsynaptic membrane→activates muscle fiber  Mediate fast ionic synaptic response (milliseconds) Metabotropic Receptor (atrial PS synapse heart)  G protein-linked achr/muscarinic achr  Activation of metabotropic G protein-linked receptor → production of α and β γsubunits →activation of K channel→membrane hyperpolarization inhibition of cardiac excitation  Mediate slow, biochemically mediated synaptic responses (seconds-minutes) A Chemical Messenger Must Meet Four Criteria to Be Considered a Neurotransmitter  Properties of a Neurotransmitter 1. It is synthesized in the presynaptic neuron. 2. It is present in the presynaptic terminal and is released in amounts sufficient to exert a defined action on the postsynaptic neuron or effector organ. 3. When administered exogenously in reasonable concentrations it mimics the action of the endogenous transmitter (for example, it activates the same ion channels or second- messenger pathway in the postsynaptic cell). 4. A specific mechanism usually exists for removing the substance from the synaptic cleft. 2 main classes of chemical substances for signaling neuroactive peptides  short polymers of amino acids small-molecule transmitters  -packaged in small electron-lucent vesicles  packaged in large dense-core (40 nm in diameter) vesicles (approximately 70–250  -release their contents through exocytosis at nm in diameter) active zones closely associated with specific Ca2+ channels peptides  release their contents by exocytosis, similar to those seen in secretory glands and mast cells.  Both types of vesicles are found in most neurons but in different proportions.  Small synaptic vesicles: -characteristic of neurons that use ACh, glutamate -aminobutyric acid (GABA), and glycine as transmitters  large dense-core vesicles - typical of neurons that use catecholamines and serotonin as transmitters.  Acetylcholine only low-molecular-weight amine transmitter substance that is not an amino acid or derived directly from one. MAJOR LOCATIONS  released at all vertebrate neuromuscular junctions by spinal motor neurons  autonomic nervous system: transmitter for all preganglionic neurons and for parasympathetic postganglionic neurons  form synapses throughout the brain; those in the nucleus basalis have particularly widespread projections to the cerebral cortex.  together with a noradrenergic component is a principle neurotransmitter of the reticular activating system, which modulates arousal, sleep, wakefulness, and other critical aspects of human consciousness Neurotransmission at Cholinergic Neurons Synthesis of acetylcholine. Storage of acetylcholine in vesicles. Release of acetylcholine. Binding to receptor. Degradation of acetylcholine. Recycling of choline. SYNTHESIS: -Choline is taken up into nerve terminals by special choline transport system mediated by a carrier that co-transports sodium. - choline transport appears to be the rate limiting step. - inhibited by hemicholinium. - choline acetylated by enzyme choline acetyl transferase to form Ach. STORAGE AND RELEASE: - Ach is packaged into vesicles by an active transport process coupled with the efflux of protons. - When an action potential propagated voltage sensitive calcium channels in the presynaptic membrane opens causes an intracellular increase of calcium. -Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and release of their contents into the synaptic cleft. -release can be blocked by botulinum toxin. DEGRADATION: -degraded by acetylcholinestrase and forms choline and acetate in the synaptic cleft. - bind to the enzyme active site. - hydrolysed to acetylated enzyme and choline Two types of acetylcholinesterase ensymes: 1. True choline estrase - Specific,essential for life - Substrate Ach, methacholine - Present in cholinergic nerve - To regenerate take 120 days - Slow turnover 2. pseudo choline estrase - non specific ,hydrolysed ester - exogenous Ach, succinyl choline -plasma, liver, intestine,CNS RBCs, skin -synthesized in liver Types of Receptors  NICOTINIC RECEPTOR  MUSCARINIC RECEPTOR -Stimulated by nicotine, on the basis of - are G protein coupled receptor their ability to be bound by natural causing occurring alkaloid nicotine Activation of phospholipase c -Has ligand gated ion channel---- Inhibition of adenylate cyclase depolarization Activation of potassium channels TWO types : Inhibition of calcium channels 1.Nm (neuromuscular junction) blocked by d-Tubo-curarine.  5 types 2. Nn (postganglionic cell body ),  Blocked by atropine blocked by hexamethonium Ionotropic Receptor (NMJ skeletal muscle)  Ach-activated ion channel/Nicotinic AchR  Activation of ionotropic receptor → rapid opening of ion channels (Na,K)→depolarization/hyperpolarization of postsynaptic membrane→activates muscle fiber  Mediate fast ionic synaptic response (milliseconds) Metabotropic Receptor  G protein-linked achr/muscarinic achr  Activation of metabotropic G protein-linked receptor → production of α and β γsubunits →activation of K channel→membrane hyperpolarization inhibition of cardiac excitation  Mediate slow, biochemically mediated synaptic responses (seconds-minutes) Catecholamine Transmitters Dopamine Norepinephrine Epinephrine  CNS: norepinephrine is used as a transmitter by neurons with cell bodies in the locus ceruleus, a nucleus of the brain stem with many complex modulatory functions  adrenergic neurons are relatively few in number, they project diffusely throughout the cortex, cerebellum, and spinal cord.  PNS: norepinephrine is the transmitter of the postganglionic neurons in the sympathetic nervous system tyrosine hydroxylase - converts tyrosine to l-dihydroxyphenylalanine (l-DOPA) - rate-limiting for the synthesis of both dopamine and norepinephrine - dopamine hydroxylase Third enzyme - converts dopamine to norepinephrine - membrane-associated - bound tightly to the inner surface of aminergic vesicles as a peripheral protein. - Norepinephrine is the only transmitter synthesized within vesicles. phenylethanolamine-Nmethyltransferase –methylates norepinephrine to form epinephrine (adrenaline) in the adrenal medulla -Not all cells that release catecholamines express all biosynthetic enzymes -cells that release epinephrine express all ensymes -neurons that release norepinephrine do not express the methyltransferase neurons that release dopamine do not express the transferase or dopamine - hydroxylase Dopamine Recpetors  There are five subtypes of dopamine receptors D1-D5  D1 and D5 increase the intracellular levels of cAMP by activating adenylate cyclase.  D2, D3, D4 decrease the intracellular levels of cAMP by inhibiting adenylate cyclase.  The effect the dopamine on a neuron depends on the receptor that is one the particular neroun. NORADRENALINE  acts mainly on α receptors  in hemodynamic disorders that are due to vasodilation (septic shock)  also cardiogenic shock ADRENALINE  acts mainly on α and β receptors  in anaphylactic shock (action on α receptors reduces oedemas and action on β2 recetors causes bronchodilation)  cardiac arrest (effect on β1 receptors in the heart)   Parkinson’s- stiffness of the body, slow movements, and trembling of the limbs. It is caused by massive loss of dopamine cells. Disease and  L-Dopa is used to treat this disease.  Dopamine drugs help treat ADHD by disorders increasing the levels of dopamine in the brain.  Pain and nausea can be increased with decreased dopamine levels in the brain.   High levels of dopamine have been observed in patients with schizophrenia.  Primary pathways affected by dopamine include an influx of levels in the mesolimbic Psychosis pathway and a decrease in levels in the mesocortical pathway. Serotonin  serotonergic neurons are found in and around the midline raphe nuclei of the brain stem  involved in regulating attention and other complex cognitive functions  Projections of these cells (like those of noradrenergic cells in the locus ceruleus) are widely distributed throughout the brain and spinal cord. Clinical implications  Serotonin and the catecholamines norepinephrine and dopamine are implicated in depression, a major mood disorder.  Antidepressant medications inhibit the uptake of serotonin, norepinephrine, and dopamine, thereby increasing the magnitude and duration of the action of these transmitters, which in turn leads to altered cell signaling and adaptations  limiting reaction: tryptophan hydroxylase Histamine  long been recognized as an autacoid, active when released from mast cells in the inflammatory reaction and in the control of vasculature, smooth muscle, and exocrine glands (eg, secretion of highly acidic gastric juice)  a transmitter in both invertebrates and vertebrates  concentrated in the hypothalamus, one of the centers for regulating the secretion of hormones CNS  regulation of drinking  body temperature PNS  secretion of antidiuretic hormone  control of blood pressure  Pain  perception of pain  itch  wakefulness Clinical use a diagnostic agent to assess nonspecific bronchial hyperreactivity in asthmatics as a positive control injection during allergy skin testing Toxicity and contraindications Flushing, hypotension,tachycardia, headache wheals, brochoconstriction, gastrointestinal upset Receptor Distribution Postreceptor Partially Selective Agonists Partially Selective Subtype Mechanism Antagonists H1 Smooth muscle, endothelium, brain Gq, IP3, DAG Histaprodifen Mepyramine, triprolidine, cetirizine H2 Gastric mucosa, cardiac muscle, mast Gs, cAMP Amthamine Cimetidine,1 raniti cells, brain dine,1 tiotidine H3 Presynaptic: brain, myenteric plexus, Gi, cAMP R--Methylhistamine, imetit, Thioperamide, other neurons immepip iodophenpropit, clobenpropit,1 tiprolisant1 H4 Eosinophils, neutrophils, CD4 T cells Gi, cAMP Clobenpropit, imetit, Thioperamide clozapine Amino Acid Neurotransmitters Glutamate and glycine not only neurotransmitters but also universal cellular constituents. can be synthesized in neurons, neither are essential amino acids.  GLUTAMATE  most frequently used at excitatory synapses throughout the central nervous system  produced from a ketoglutarate, an intermediate in the tricarboxylic acid cycle of intermediary metabolism.  After it is released, glutamate is taken up from the synaptic cleft by specifc transporters in the membrane of both neurons and glia  glutamate taken up by astrocytes is converted to glutamine by the enzyme glutamine synthase  glutamine then diffuses back into neurons that use glutamate as a transmitter, where it is hydrolyzed back to glutamate.  Phosphate-activated glutaminase (PAG), which is present at high concentrations in these neurons, is responsible for salvaging the molecule for reuse as a transmitter  Glycine neurotransmission major transmitter used by inhibitory interneurons of the spinal cord an allosteric modulator of the N- methyl-d-aspartate (NMDA) subtype of glutamate receptors synthesized from serine. specific biosynthesis in neurons is not well understood, but its biosynthetic pathway in other tissues is well known  Summary of Glycine synthesis, release, reuptake, degradation 1. Glycine is synthesized from serine by SHMT 2. Glycine is packaged into synaptic vesicles by VIAAT (same transporter as for GABA) 3. Glycine is removed from synapse by GLYT1 (glial, for clearance from synapse), and GLYT2 (neuronal, for re- uptake and packaging). 4. Glycine is cleaved by the GCS: glycine cleavage system glycine cleavage system Consists of 4 proteins T protein L protein H protein P protein GABA  present at high concentrations throughout the central nervous system  used as a transmitter by an important class of inhibitory interneurons in the spinal cord.  brain GABA is the major transmitter of various inhibitory neurons and interneurons, such as the medium spiny neurons of the striatum, striatal interneurons, basket cells of both the cerebellum and the hippocampus, the Purkinje cells of the cerebellum, granule cells of the olfactory bulb, and amacrine cells of the retina.  Whereas glutamate is the principal excitatory neurotransmitter, GABA is the principal inhibitory neurotransmitter in the brain A typical GABA presynaptic terminal  Summary of GABA synthesis, release, reuptake, degradation 1. GABA is formed by removal of carboxyl group of glutamate, by the enzyme GAD 2. GABA is packaged into synaptic vesicles by VIAAT and released by depolarization 3. GABA may be taken up by nerve terminal by GAT proteins for repackaging into synaptic vesicles 4. GABA may be taken up by glial cells, where it undergoes reconversion to glutamate (amine group is transferred to a- ketoglutarate, generating glutamate and succinic semialdehyde) 5. Glutamate is transported back into nerve terminal, where it serves as precursor for new GABA synthesis GABA receptors: Fast GABA transmission mediated mainly by GABAA receptors, which are ligand-activated chloride channels. Some fast GABA transmission mediated by so-called GABAC receptors, which are a closely-related sub-family of GABAA receptors GABA also utilizes a metabotropic receptor called the GABAB receptor, described in Neuromodulation section. Neuroactive Peptides Serve as Transmitters