Synaptic Transmission PDF

SYNAPTIC TRANSMISSION Synapse: unique junction that mediates information flow from one neuron to another or effector cell…  Functional Types of Synapes Two main classes of synapses are distinguished; Electrical synapses Electrical synapses allow current to flow from one...

SYNAPTIC TRANSMISSION Synapse: unique junction that mediates information flow from one neuron to another or effector cell…  Functional Types of Synapes Two main classes of synapses are distinguished; Electrical synapses Electrical synapses allow current to flow from one excitable cell to the next via low resistance pathways between the cells called gap junctions ( i.e.; cardiac muscle, some kinds of smooth muscle like uterus or bladder ). Chemical synapses In chemical synapses, there is a gap between the presynaptic cell membrane and the postsynaptic cell membrane, known as the synaptic cleft. Information is transmitted across the synaptic cleft via a neurotransmitter, a substance that is released from the presynaptic terminal and binds to receptors on the postsynaptic terminal. A. Electrical synapses Direct transfer of ionic current from one cell to the next Gap junction The membranes of two cells are held together by clusters of connexins Connexon A channel formed by six connexins Two connexons combine to form a gap junction channel Allows ions to pass from one cell to the other 1-2 nm wide : large enough for all the major cellular ions and many small organic molecules to pass  Cells connected by gap junctions are said to be ‘electrically coupled’. Flow of ions from cytoplasm to cytoplasm bidirectionally Very fast, fail-safe transmission Often found where normal function requires that the neighboring neurons be highly synchronized Common in mammalian CNS as well as in invertebrates Electrical coupling of neurons has been demonstrated for most brain regions, including the inferior olive, cerebellum, spinal cord, neocortex, thalamus, hippocampus, olfactory bulb, retina, and striatum. B. Chemical synapses B. Chemical synapses Neurotransmitter Synthesis and Storage Principles of Chemical Synaptic Transmission Basic Steps Neurotransmitter synthesis Load neurotransmitter into synaptic vesicles Vesicles fuse to presynaptic terminal Neurotransmitter spills into synaptic cleft Binds to postsynaptic receptors Biochemical/Electrical response elicited in postsynaptic cell Removal of neurotransmitter from synaptic cleft HOW  Neurotransmitter Release Voltage-gated calcium channels open - rapid increase from 0.0002 mM to greater than 0.1 mM Exocytosis can occur very rapidly (within 0.2 msec) because Ca2+ enters directly into active zone − ‘Docked’ vesicles are rapidly fused with plasma membrane − Protein-protein interactions regulate the process (SNAREs) of ‘docking’ as well as Ca2+- induced membrane fusion − Vesicle membrane recovered by endocytosis V-SNARES; Synaptobrevin, Synaptotagmin T-SNARES; SNAP-25, Syntaxin Synaptotagmin is the Ca++ sensor  Synaptic vesicles are recycled by an endocytotic pathway commonly found in most cell types. Coated pits are formed in the plasma membrane, which then pinch off to form coated vesicles within the cytoplasm of the presynaptic terminal. These vesicles then lose their coat and undergo further transformations to become once again synaptic vesicles ready for release. Termination of Neurotransmitter Effects Neurotransmitter bound to a postsynaptic neuron: Produces a continuous postsynaptic effect Blocks reception of additional “messages” Must be removed from its receptor Removal of neurotransmitters occurs when they: Are degraded by enzymes Are reabsorbed by astrocytes or the presynaptic terminals Diffuse from the synaptic cleft Synaptic Delay Neurotransmitter must be released, diffuse across the synapse, and bind to receptor Synaptic delay – time needed to do this (0.3-5.0 ms) Synaptic delay is the rate-limiting step of neural transmission Postsynaptic Potentials Excitatory and Inhibitory Postsynaptic Potentials EPSP:Transient postsynaptic membrane depolarization by presynaptic release of neurotransmitter Ach- and glutamate-gated channels cause EPSPs  IPSP:Transient hyperpolarization of postsynaptic membrane potential caused by presynaptic release of neurotransmitter Glycine- and GABA-gated channels cause IPSPs Synaptic Integration Basic principle of neural computation Process by which multiple synaptic potentials combine within one postsynaptic neuron The combining of excitatory and inhibitory signals acting on adjacent membrane regions of a neuron. In order for an action potential to occur, the sum of excitatory and inhibitory postsynaptic potentials (local responses) must be greater than a threshold value. Neurotransmitters  Acetylcholine (ACh) Releases from all preganglionic and most postganglionic neurons in the parasympathetic nervous system and from all preganglionic neurons in the sympathetic nervous system. Ach is the transmitter at neuromuscularjunction and also within the CNS Nicotinic ACh receptors Ionotrophic; nonselective cationic channel  Muscarinic ACh receptors There are five known muscarinic subtypes of ACh receptors (M1 to M5). All are metabotropic receptors; however, they are coupled to different G proteins and can thus have distinct effects on the cell M1, M3, and M5 are coupled to pertussis toxin-insensitive G proteins, whereas M2 and M4 are coupled to pertussis toxin-sensitive G proteins Each set of G proteins is coupled to different enzymes and second messenger pathways  Glutamate Glutamate, an amino acid, is the major excitatory neurotransmitter in the central nervous system glutamate-glutamine cycle  Glutamate has both ionotropic and metabotropic receptors Based on pharmacological properties and subunit composition, several distinct ionotropic receptor subtypes are recognized: AMPA, Kainate and NMDA AMPA-gated channels are found in most excitatory synapses in the brain, and they mediate fast excitation. NMDA-gated channels have more complex behavior. The ion selectivity of NMDA channels is the key to their functions: permeability to Na+ and K+ causes depolarization and thus excitation of a cell, but their high permeability to Ca2+ allows them to influence [Ca2+]i Ca2+ can activate many enzymes, regulate the opening of a variety of channels, and affect the expression of genes. Excess Ca2+ can even precipitate the death of a cell. ❖ The combination of voltage sensitivity and Ca2+ permeability of the NMDA channels has led to hypotheses concerning their role in learning and memory- related functions. ❖NMDA-gated channels coexist with AMPA-gated channels in many synapses of the brain.  Eight genes coding for metabotropic glutamate receptors have been identified and classified into three groups. Group I receptors are found mainly postsynaptically, whereas groups II and III are found mainly presynaptically.  Inhibitory Amino Acid Receptors: GABA and Glycine Both glycine and GABA (GABAA and GABAC) have ionotropic receptors Each of these receptors has a Cl- channel Probability of these channels opening and the average time that a channel stays open are controlled by the concentration of the neurotransmitter for which the receptor is specific. ✓ Glycine-mediated inhibitory synapses predominate in the spinal cord, whereas GABAergic synapses make up the majority of inhibitory synapses in the brain.  GABAA receptors are the targets of two major classes of drugs: benzodiazepines and barbiturates. Benzodiazepines are widely used antianxiety and relaxant drugs. Barbiturates are used as sedatives and anticonvulsants. Both classes of drugs bind to distinct sites on the α subunits of GABAA receptors and enhance opening of the receptors' Cl- channels in response to GABA.  The GABAB receptor is a metabotropic receptor. Binding of GABA to this receptor activates a heterotrimeric GTP-binding protein which leads to activation of K+ channels and hence hyperpolarization of the postsynaptic cell, as well as inhibition of Ca++ channels (when located presynaptically) and thus a reduction in release of transmitter. Glycine 1. Overview Glycine is another inhibitory neurotransmitter, predominantly found in the spinal cord, brainstem, and retina. Like GABA, glycine helps maintain the balance between excitation and inhibition, especially in the spinal cord. 2. Synthesis and Release Synthesis: Glycine is synthesized from the amino acid serine by the enzyme serine hydroxymethyltransferase. Storage and Release: Glycine is packaged into vesicles in presynaptic neurons and released into the synaptic cleft upon arrival of an action potential. 3. Glycine Receptors Glycine Receptors (GlyRs): Type: Ionotropic receptors (ligand-gated chloride channels). Mechanism: When glycine binds to GlyRs, Cl⁻ channels open, allowing Cl⁻ to flow into the neuron and cause hyperpolarization. Function: Hyperpolarization inhibits the postsynaptic neuron, reducing the likelihood of action potential generation. Modulatory Role in NMDA Receptors: Glycine also serves as a co-agonist with glutamate at NMDA receptors in the CNS. This interaction is necessary for NMDA receptor activation, which is involved in learning and memory. 4. Role of Glycine in the CNS Glycine primarily provides inhibitory control in the spinal cord, helping to regulate motor functions and prevent excessive excitatory activity. It plays a significant role in reflexes and sensory processing in the spinal cord and brainstem.  Biogenic Amines Among the amines known to act as neurotransmitters are; Dopamine Norepinephrine (noradrenaline), Epinephrine (adrenaline), Serotonin (5-hydroxytryptamine [5-HT]) ✓ Dopamine, norepinephrine, and epinephrine are catecholamines, and they share a common biosynthetic pathway that starts with the amino acid tyrosine. The catecholamines are degraded by two enzymes, mitochondrial monoamine oxidase (MAO) and cytosolic catechol O-methyltransferase (COMT). Dopamine Dopamine is involved in many processes, including mood regulation, reward and pleasure pathways, motor control, and the regulation of hormonal responses. The cell bodies of dopaminergic neurons are highly concentrated in the midbrain. Their axons project to different parts of the brain and can be divided into two systems: the nigrostriatal dopamine system, involved in motor control, and the mesolimbic dopamine system, involved in emotional reward Norepinephrine Norepinephrine (also known as noradrenaline) is a neurotransmitter and hormone that plays a critical role in the body’s response to stress and various physiological processes.  Serotonin Serotonin is a neurotransmitter that plays a vital role in regulating various physiological and psychological processes in the body. Functions: Serotonin is primarily known for its influence on mood, emotion, and behavior. It helps regulate mood stability, anxiety levels, and overall feelings of well-being. It's often referred to as the "happiness hormone" because of its association with feelings of happiness and contentment. Mood Regulation: Low levels of serotonin are linked to mood disorders, including depression and anxiety. Many antidepressant medications, such as selective serotonin reuptake inhibitors (SSRIs), work by increasing serotonin levels in the brain. Physiological Roles: In addition to its effects on mood, serotonin is involved in several bodily functions, including: Digestion: Approximately 90% of the body’s serotonin is found in the gastrointestinal tract, where it regulates bowel movements and function. Sleep: Serotonin is a precursor to melatonin, the hormone that regulates sleep-wake cycles. It plays a role in promoting sleep and influencing sleep quality. Appetite: Serotonin helps regulate appetite and feelings of satiety, influencing food intake and cravings. Cognition: Serotonin also affects cognitive functions, including memory and learning. Adequate serotonin levels are important for optimal cognitive performance. Pain Perception: Serotonin modulates pain perception in the nervous system, influencing how pain is experienced and processed. Mood Disorders: Conditions like depression, anxiety, and obsessive-compulsive disorder (OCD) are often associated with dysregulation of serotonin levels. Biogenic Amine Receptors With the exception of one class of serotonin receptors (5-HT3), the receptors for the various biogenic amines are all metabotropic-type receptors. Thus, these neurotransmitters tend to act on relatively long time scales by generating slow synaptic potentials and by initiating second messenger cascades. Agonists and blockers of many of these receptors are important clinical tools for treating various neurological and psychiatric disorders. Serotonin receptors (5-hydroxytryptamine; 5-HT receptors)  Serotonin receptors (5-hydroxytryptamine; 5-HT receptors) Thank You….