General Principles of Chemical Transmission PDF

General Principles of Chemical transmission Prof M. Moshi  General Principles of Chemical Transmission Learning Objectives Brief historical review of signal transmission Differentiate between electrical and chemical transmission Describe the synthesis, stor...

General Principles of Chemical transmission Prof M. Moshi  General Principles of Chemical Transmission Learning Objectives Brief historical review of signal transmission Differentiate between electrical and chemical transmission Describe the synthesis, storage and release of chemical transmitters Describe the process of chemical synaptic transmission termination of a chemical signal Describe retrograde chemical transmission The History of Chemical Transmission Understanding of the function of living organism emanates from the middle of the 19th century through studies in experimental physiology The peripheral nervous system (PNS), and, particularly the autonomic nervous system (ANS) received a lot of attention It was then observed that electrical stimulation of nerves could elicit a variety of physiological effects from blanching of the skin to cardiac arrest  The History of Chemical Transmission By 1869 it had been shown that muscarine could mimic the effects of stimulating the vagus nerve and atropine could inhibit the effects of both muscarine and electrical stimulation Du Bois-Raymond (1877) explained the concept of neurotransmission using two statements:- Of known natural processes that might pass on excitation, only two are, in my opinion, worth talking about:  (a) either there exists at the boundary of the contractile substance a stimulatory secretion or  (b) the phenomenon is electrical in nature The History of Chemical Transmission In 1904 Elliot suggested that adrenaline might act as a chemical transmitter mediating the actions of sympathetic nervous system. This was not well received In 1905 Langley (Prof of Physiology) showed the same for nicotine and curare acting at neuromuscular junction. He suggested that transmission to skeletal muscle involved the secretion by the nerve terminals of a substance related to nicotine Most physiologists interpreted these effects as stimulation and inhibition of nerve endings rather than as evidence for chemical transmission The History of Chemical Transmission One of the key observations made by Elliot was that degeneration of sympathetic nerve terminals did not abolish the sensitivity of smooth muscle preparations to adrenaline but enhanced it This is what was predicted by the electrical theory  Synaptic transmission A synapse is a site where information is transmitted from one cell to another Two main classes of synapses are distinguished; electrical and chemical synapses. 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 to another neuron or non-neuronal tissue.  Electrical Synapses Involve direct transfer of ionic current from one cell gap junction to the next cell 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  Electrical Synapses Cells connected by gap junctions are said to be ‘electrically coupled’ and they act as ‘low-pass filters’. Allow flow of ions from cytoplasm to cytoplasm bidirectionally Common in mammalian CNS as well as in invertebrates  Chemical synapses Chemical synapses occur between different parts of neurons There are four types of chemical synapses:-  Axon to dendrite (axodendric)  Axon to cell body (axosomatic)  Axon to axon (axoaxonic)  Dendrite to dendrite (dendrodendritic) Chemical Synapses Electrical synapses  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  Retrograde Chemical Transmission In a few cases, retrograde transmission may occur from the postsynaptic cell to the presynaptic neuron terminal and modify its subsequent activity. Neurotransmitter Synthesis and Storage  Neurotransmitter Release 1. When AP arrives vesicles loaded with neurotransmitters are rapidly fused with the plasma membrane 2. Voltage-gated calcium channels open leading to a rapid intracellular [Ca2+] increase from 0.0002 mM to greater than 0.1 mM 3. Release of neurotransmitters by exocytosis occurs very rapidly (within 0.2 msec) because Ca2+ enters directly into active zone 4. Vesicle membranes are then recovered by endocytosis  Recycling of Synaptic vesicles Synaptic vesicles are recycled by an endocytic 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. Clathrin is a protein that plays a role in the formation of coated vesicles  Neurotransmitter Recovery and Degradation Clearing of neurotransmitter is necessary for the next round of synaptic transmission Neurotransmitters re-enter presynaptic axon terminals through transporter proteins Some of neurotransmitters in the synaptic cleft undergo enzymatic destruction e.g acetylcholine by acetylcholinesterase (AchE) Desensitization: Channels close despite the continued presence of ligand Can last several seconds after the neurotransmitter is cleared Nerve gases (e.g. sarin) inhibit AchE --- increased Ach ---- AchR desensitization ---- muscle paralysis Neostigmine, pyridostigmine, physostigmine – AchE inhibitors  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  Synaptic Receptors Ionotropic receptors Metabotropic receptors  Ionotropic receptors Ligand (Transmitter)-gated ion channels Ligand-binding causes a slight conformational change that leads to the opening of channels Not as selective to ions as voltage-gated channels Depending on the ions that can pass through, channels are either excitatory or inhibitory  Metabotropic receptors G-protein-coupled receptors Trigger slower, longer- lasting and more diverse postsynaptic actions Same neurotransmitter could exert different actions depending on receptor subtypes Neurotransmitter Receptor Mechanisms Second Messenger System Neurotransmitters (Amino acids, Amines and Peptides)  Acetylcholine It is also the neurotransmitter that is released from presynaptic neurons of the adrenal medulla. Released from all preganglionic and most postganglionic neurons in the parasympathetic nervous system and from all preganglionic neurons in the sympathetic nervous system.  Nicotinic ACh receptors Ionotrophic; nonselective cationic channel trophic; 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 Distribution and Functions of Muscarinic Receptors In CNS M1; EPSP in autonomic ganglia M3; Smooth muscle contraction Secretion from salivary glands Bronchoconstriction and stomach Increase intracellular calcium in vascular endothelium In CNS Increased endocrine and exocrine gland secretions, M2; Slow heart rate (e.g. salivary glands and Reduce contractile forces of stomach) atrium In CNS Reduce conduction velocity of AV node Eye accommodation Vasodilation Induce emesis  Distribution and Functions of Muscarinic Receptors M4; In CNS Produce generally inhibitory effects M5; In CNS Location of M5 receptors is not well known Distribution and Functions of Muscarinic Receptors Distribution and Functions of Muscarinic Receptors  Glutamate Glutamate, an amino acid, is the major excitatory neurotransmitte r in the central nervous system  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