Neuromuscular Junction and Synaptic Transmission PDF

# Types of Synapses ## 1. Electrical Synapses - Current flows cell to cell via low resistance pathways: Gap Junctions - Found in Muscle cells and in Some smooth muscle cells - Allows for fast conduction and coordinated contraction - Examples: Cardiac ventricular muscle, uterus, bladder - Bidirect...

# Types of Synapses ## 1. Electrical Synapses - Current flows cell to cell via low resistance pathways: Gap Junctions - Found in Muscle cells and in Some smooth muscle cells - Allows for fast conduction and coordinated contraction - Examples: Cardiac ventricular muscle, uterus, bladder - Bidirectional ## 2. Chemical Synapses - Information transmission happens from Presynaptic cell membrane to Postsynaptic Cell membrane. Between those membranes there is synaptic cleft - space which chemical (neurotransmitter) must pass. - Neurotransmitter - Chemical which passes from presynaptic membrane to postsynaptic membrane. Depending on effect on postsynaptic cell we have two types of neurotransmitter: Excitatory and Inhibitory. If the neurotransmitter is excitatory it causes depolarization of postsynaptic membrane, if it is inhibitory it causes hyperpolarization. - At the end of action potential Ca+ influx happens in presynaptic membrane and as a result vesicle in which we have our neurotransmitter is released by exocytosis from the cell membrane - Unlike Electrical synapses, chemical synapses is unidirectional. - Synaptic Duct - time required for neurotransmission from cell to cell. ## Neuromuscular Junction-Example of a Chemical Synapse ### Motor Units - Motoneuron (neuron innervating muscle) + muscle fibers - Small motor units for fine motor activities like facial expression and Large motor units for gross muscular activities like quadriceps muscles used in running. ### Sequence of Events at the Neuromuscular Junction 1. Action potential is propagated across neuron -->each site is depolarized consequently=> current reaches site of Calcium voltage gated channels and opens them 2. Calcium flows into the terminal down its electrochemical gradient. 3. Because of this vesicle fuses with membrane and releases acetylcholine with its contents like proteoglycan and ATP into synaptic clept - Acetylcholine = Acetyl coenzyme A + Choline. Acting enzyme: choline acetyltransferase - the release of ACh is quantal, meaning least amount of ACh that can be released is content which is in one vesicle. 4. acetylcholine binds to alfa subunit of nicotinic receptor of motor end plate of postsynaptic membrane, which causes conformational change of Na/K Channells => influx of sodium and efflux of potassium ions - Motor end plate - specialized region of muscle cell membrane (sarcolemma), which contains nicotinic receptors, of postsynaptic membrane - Nicotinic Receptors - receptors on ligand gated Na+ and K+ channels. 5. Influx and efflux of sodium and potassium respectively causes end plate potential which is -90mv to be increased at -50 mv which is threshold level. this happens because there are other ion channels like leaky channels and Na/K Pumps that also influence the electrochemical gradient across the membrane, hypotehtically without this channels, potential difference would become 0. - miniature end plate potential (MEPP) - potential difference caused by one vesicle which is 0.4 mv, end plate potential is summation of these MEPPs - We would need approximately 100 quanta or vesicle to reach depolarized potential of -50 mv 6. This depolarization of sarcoplasmic membrane would spread alond the muscle fibers and caused those parts to have threshold and thus to propagate action potential 7. The EPP at the motor end plate ends when ACh --> choline and acetate by acetylcholinisterase. - 50% percent of choline is returned to presynaptic membrane by Na+ choline cotransport. ## Agents altering neuromuscular function 1. Botulinis Toxin - blocks transfer of ACh from presynaptic membrane - paralyisis of skeletal muscle - death from respiratory failure 2. Curare- competes with ACh for nicotinic receptors, decreasing the size of EPP as a result plus paralysis and death - D-tubocurarine - form of curare which is used in anesthesia for relaxation. - alfa - bungarotoxin - binds irreversibly to receptors, we can measure densiiy of those receptors by radioactive form of it. 3. AChE Inhibitors (antiocholinestarases) - "neostigmine" is an example of it - this blocks degradation of acetylcholine thus,enhancing the action of acetylcholine. - myasthania gravis - neostigmine can be used in this disorder where antibodies block receptors causing weakness and stuff. 4. Hemicholinium - decreases synthesis of acetylcholine by blocking reuptaking of choline by presynaptic membrane. # Types of synaptic Arrangements There are cases where we need not one-one cell connection but one to many or many to one cell connection in order for presynaptic cell(s) to depolarize postsynaptic cell(s): summationf of these many synapses then become enough to fire action potential along postsynaptic cell(s). Many to one synaptic arrangements can be excitatory and inhibitory, depending on type of neurotransmitter. ## Excitatory postsynaptic potetntials: - Excitatory postsynaptic potentials (EPSPs) are synaptic inputs that depolarize postsynaptic cell leading to threshold potential. - produced by Ligand gated Na+ and K+ channels. - Examples: ACh, norepinephrine,epinephrine,dopamine,glutamate and serotonin ## Inhibitory postsynaptic potentials - IPSPs are synaptic inputs hyperpolarizing the postsynaptic membrane --> Action potential is not generated - produced by Chlorine Anion channels (equlibrum potential approximately -90mv) - Inhibitory neurotransmitters: gama-aminobutyric acid (GABA) and glycine ## Integration of Synaptic Information Information arriving at postsynaptic membrane can be integrated in two ways: spatially and temporally. ### Spatial Summation - occurs when two or more presynaptic inputs arrive at the same time on postsynaptic membrane - If those cells produce EPSPs then we get summation of their effect on cell membrane - If there are EPSP and IPSP producing cells they will cancel out each other - Due to fast conduction of potentials spatial summation occurs even when inputs are far apart on the nerve cell body ### Temporal Summation - Inputs arrive on membrane in succesion, overlapping each other and summating as a result ## Other phenomena That Alter Synaptic Activity - Facilitation, Augmentation, post-tetanic potentiation - Accumulation of calcium in presynaptic membrane causes increase release of neurotransmitters as a result response of postsynaptic cell membrane is greater than expected (meaning depolarization is greater probably) - Long Term potentiation - increased release of neurotransmitter and increase response from postsynaptic membrane in memory cells - Synaptic Fatigue - possibly* depletion of neurotransmitter causes smaller than expected response in the postsynaptic cells. ## Neurotransmitter ### How can we classify something as the Neurotransmitter? 1. Substance is synthesized in presynaptic cells 2. Substance is released on stimulation 3. if it is applied at physiologic concentration we have response from postsynaptic membrane mimicing in vivo response. ### Groups of neurotransmitters: acetylcholine, biogenic amines, amino acids, neuropeptides | Choline Esters | Biogenic Amines | Amino Acids | Neuropeptides | |---|---|---|---| | Acetylcholine (ACh) | Dopamine | y-Aminobutyric acid (GABA) | Adrenocorticotropin (ACTH) | | | Epinephrine | Glutamate | Cholecystokinin | | | Histamine | Glycine | Dynorphin | | | Norepinephrine | | Endorphins | | | Serotonin | | Enkephalins | | | | | Glucose-dependent insulinotropic peptide (GIP) | | | | | Glucagon | | | | | Neurotensin | | | | | Oxytocin | | | | | Secretin | | | | | Substance P | | | | | Thyrotropin-releasing hormone (TRH) | | | | | Vasopressin | | | | | Vasoactive intestinal peptide (VIP) | ## Acetylcholine - Only neurotransmitter at the neurmoscular junction - In Parasymphatetic nervous system: released from all preganglionic and most postganglionic neurons - In symphatetic nervous system: released from all preganglionc neurons ### Synthetic and Degradative pathways: - Synthesis in presynaptic terminal: choline + acetyl CoA catalyzed by choline acetyltrasnferase. - In postsynaptic membrane binds and activates nicotinic ACh receptors - acetylcholineesterase degrades ACh on postsynaptic membrane **Figure 1-17 Synthesis and degradation of acetylcholine.** ## Norepinephrine, Epinephrine and Dopamine - Share the same precurson: tyrosine and they are each's past selfs: tyrosine becomes dopamine which becomes norepinephrine which becomes epinephrines - Tyrosine --> I-dopa (enzyme: tyrosine hydroxilase ) --> dopamine (enzyme: dopa decarboxylase ) --> norepinephrine (in vesicles if we have beta-hydroxylase) ---> epinephrine (methylation by phenylethanolamine-N-methyltrasnferase with S-adenosylmethionine) - dopaminergic neurons - secrete dopamine - adrenergic neurons - secrete norepinepinephrine, - adrenal medulla - secretes primarily epinephrine ### The degradative enzymes: 1. Catechol-O-methyltransferase (COMT): found in liver cells. 2. monoamine oxidase (MAO): found in nerve terminals. both enzyme can act independently and cooperatively leading to 3 different metabolite for each biogenic amine ### Metabolites: - norepinephrine - normetanephrine - epinephrine - metanephirne - both are also degraded to - : 3-methoxy-4-hydroxymandelic acid (VMA) **Figure 1-18 Synthesis and degradation of dopamine, norepinephrine, and epinephrine. COMT, Catechol-O-methyltransferase; MAO, monoamine oxidase.** ## Serotonin - Produced from tryptophan in serotonergic neurons of brain and in gastrointestinal tract - may be returned intact or degraded in presynaptic terminal by monoamine oxidase (just like norepinephrine, epinep.., dopamine) into 5-hydroxyindoleacetic acid precursor to melatonin in pineal gland (epiphysis) **Figure 1-19 Synthesis and degradation of serotonin. MAO, Monoamine oxidase.** ## Histamine - Produced from histidine from histidine decarboxylase - Present in hypothalamus and in mast cells of gastrointestinal tract ## Glutamate - Major excitatory neurotransmitter in central nervous sytem (spinal cord and cerebellum) - 4 subtype glutamate receptors: - 1-3 subtype: ionotropic receptors like NMDA (N-methyl-D-aspartate), a lot in central nervous sysyem. - 4th subtype: metabotropic receptors coupled by G proteins (hetero GTP binding) ## Glycine - Inhibitory neurotransmitter which causes increase in Chlorine conductance inside cells leading to hyperpolarization. ## y-Aminobutyric Acid (GABA) - Inhibitory neurotransmitter in GABAergic Neurons in CNS. - Synthesized from glutamic acid by enzyme: glutamic acid decarboxylase. - Either recycled back or degraded GABA Transaminase to enter cytric acid cycle - GABAa and GABAb receptors - 1. GABAa: Increase Chlorine influx => ionotropic receptor - 2. GABAb : Increase Potassium efflux and is Coupled by G proteins => metabotropic receptors. - Huntington Disease - GABA deficinecy associated with hyperkinetic choreiform movements related to a deficiency. **Figure 1-20 Synthesis and degradation of y-aminobutyric acid (GABA).** ## Nitric Oxide (NO) - in CNS and in gastrointestinal tract - NO synthase synthesizes it from arginine (citruline is another porduct of this conversion) - Diffuses withou packaging in vesicles - acts in signal transduction of guanylyl cyclase in like vascular smooth muscle ## Neuropeptdies - Neuromodulators: alters the amount of neurotransmitters released and cosecretes with neurotransmitter to alter the response of postsynaptic vesicle - ATP with norepinephrine in symphatetic nerve junction to vascular smooth muscle. - Neurohormones - transferred in blood to act at a distant site - examples of neuropeptdies secreted with neurotransmitters (not really relevant to know?) - 1. Vasoactive intestinal peptide - acetylcholine - 2. Somatostatin,enkephalin,eurotensin with norepinphrine - 3. Substance P with serotonin - Syntehsized in nerve cell --> signal peptide sequence removed in endoplasmic reticulum --> final peptide to secretory vesicle in Golgi --> this vesicle becomes synaptic vesicle