Synaptic transmission

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  1. There are two major types of synapses: electrical (gap junctions) and chemical
    1. electrical synapses (seen in smooth muscle, conduction in the heart, vestibular nuclei of brainstem, retina – are formed by the close proximity of neurons)
      1. have no synaptic delay
      2. resistant to anoxia
      3. important in synchronization of responses
      4. no plasticity
      5. are bidirectional
    2. chemical synapses (most nervous system synapses)
      1. have a synaptic delay as electric potential is converted into chemical release
        1. delay is typically 0.5 msec which is the time for neurotransmitter to be released; a major component of this is the time it takes for the Ca channels to open
      2. sensitive to oxygen deficit
      3. important in plasticity
      4. may result in excitation or inhibition of postsynaptic cell
    3. Synaptic transmission between nerves may be excitatory or inhibitory while synaptic transmission between nerve and muscle is always excitatory
      1. Synaptic transmission between two nerves that are inhibitory are referred to as type II synapses (e.g. basket cells in the cerebellum)
  2. Steps in chemical synaptic transmission
    1. action potential invades and depolarizes the presynaptic terminal
    2. depolarization of the presynaptic terminal causes calcium ions to enter the presynaptic terminal
      1. calcium is the only essential element in synaptic transmission (Na and K are not necessary)
    3. The increased calcium ion concentration causes synaptic vesicles to fuse with special sites on the presynaptic membrane and release neurotransmitter (increases the probability that a quanta of neurotransmitter will be released)
      1. Increasing the extracellular Ca does not change the size of spontaneous miniature end plate potentials (MEPP) or the unit synaptic potentials, rather it increases the probability that a synaptic vesicle will discharge its transmitter, so that action potentials evoke fewer failure and higher amplitude postsynaptic potentials
        1. NOTE: the size of postsynaptic potentials is dependent upon the number of cells converging into a given region with the largest potentials following stimulation of the cortical regions of the distal musculature
      2. Even when there is no presynaptic stimulation there are small spontaneous potentials of about 0.5-1.0 mv called miniature end plate potentials (MEPPs)
        1. The effect of drugs on MEPPs is no different from the end plate potential evoked by nerve stimulation – MEPPs are enhanced and prolonged by prostigmine (by inhibiting the hydrolysis of Ach by acetylcholinesterase) and blocked by tubocurare
        2. A single ACh receptor channel will only cause a potential of .5 microvolts or about 1/2000 of a MEPP; for a single channel to open, two ACh molecules must bind to the receptor and some ACh never reaches the receptor thus it takes around 5,000-10,000 molecules of ACh to produce a MEPP (one quanta produces one MEPP)
    4. neurotransmitter diffuses across the synaptic cleft and reacts with specific receptors on the postsynaptic membrane
    5. the permeability of the postsynaptic membrane to various ions is changed (either increased or decreased) leading to depolarization or hyperpolarization
    6. neurotransmitter is removed from the cleft either by enzyme degredation, active uptake or diffusion
  3. Fast and slow synaptic potentials
    1. if the receptor itself contains the ion channel, the postsynaptic depolarization or hyperpolarization will be fast (e.g. nicotinic cholinergic responses)
    2. slow postsynaptic potentials are generated by channels that are removed from the receptor site and are coupled to it by various second messengers (e.g. muscarinic cholinergic respones in parasympathetic activation)
    3. most of the synapses for excitatory action are located on the dendrites while most of the inhibitory action synapses (conducting K and Cl that shunts out the capacitance current generated in the dendrites and axons) are located on the axon near the cell body
      1. Remember: each nerve essentially has an analog portion in the dendrites and axon that sum up all the excitatory and inhibitory impulses, and a digital portion (the axon hillock) that either fires or doesn’t fire depending on whether the summed potentials have crossed the threshold
  4. Skeletal neuromuscular synapses
    1. only known transmitter at the skeletal neuromuscular junction is acetylcholine which causes a rapid simultaneous increase in the postsynaptic membrane conductance to Na and K leading to depolarization; this potential change activates voltage gated Ca channels in the membrane of the sarcoplasmic reticulum leading to muscle contraction
    2. basic unit for skeletal motor action is the motor unit consisting of a single motor neuron and all the muscle fibers that it innervates
      1. Note: in myasthenia gravis patients make antibodies to their own acetylcholine receptors at the neuromuscular junction
  5. Central nervous system synapses
    1. there are over 20 CNS neurotransmitters; all either excite (e.g. glutamate), inhibit (e.g. GABA) or modulate (e.g. NE) other neurotransmitters
    2. synapses have receptors for either ligand gated channels, voltage gated channels or G-protein linked receptors
  6. Ion channel and receptor basics
    1. ion channels are either open (gap junctions) or closed (gated); those that are closed are opened by either voltage changes or ligand attachment
    2. gap junctions
      1. couple electrical signals from cell to cell resulting in synchronous behavior
      2. comprised of 6 subunits each with 4 transmembrane domains. The six subunits form a cylindrical channel
    3. voltage gated ion channels
      1. opened by changes in transmembrane voltage (e.g. voltage gated Na channels that initiate and propogate the action potential)
      2. comprised of 4 subunits each with 6 transmembrane domains. The 4 units form a box-like channel – channel rotates and opens to ions when sensing changes in voltage
    4. ligand gated ion channels
      1. gated by neurotransmitter binding to the receptor (e.g. nicotinic acetylcholine receptor at the neuromuscular junction)
      2. comprised of 5 subunits each with 4 transmembrane domains that form a cylindrical channel
    5. G-protein linked receptors
      1. Not directly associated with an integral ion channel
      2. When activated by ligand binding to the receptor, the G-protein is activated and sets off a cascade that results in ion channel gating (e.g. NE receptor which uses cAMP as a second messenger to open a K channel)
      3. Second messenger can also signal other pathways like gene expression
      4. Comprised of 1 subunit with 7 transmembrane domains
    6. Remember: subunits and domains go in alphabetical order and in descending ‘height’ – Gap junctions 6’4”, Ligand gated 5’4”, Voltage gated 4’6”: G proteins are easy to remember because there is only one protein with 7 transmembrane domains
  7. Signal transduction cascades – neurotransmitters are the first messengers while the second messengers fall into two groups, G-proteins and Ca mediated cascades; G-protein cascades include cAMP, phosphoinositol metabolites and eicosanoids
    1. G-protein mediated transduction
      1. A class of GTP (guanosine triphosphate) binding proteins consisting of alpha, beta and gamma subunits with a GDP bound to the alpha subunit; when activated, the alpha subunits affinity for the beta/gamma subunit decreases
      2. When activated by the receptor with which it is affiliated, GDP is replaced by GTP (hydrolysis of bound GTP to GDP inactivates the G protein), the G-protein splits into a soluble alpha subunit which then activates or inhibits its substrate. The beta/gamma subunit either remains membrane bound or can become an active agent in the cascade; the beta/gamma subunit stabilizes the binding of GDP and inhibits the binding of GTP; activation of any G-protein will inhibit the activation of other G proteins in the membrane
      3. Examples of better understood second messenger systems mediated by G-proteins - Protein kinases, inositol triphosphate, and protein kinase C – NE via a G protein activated phospholipase C
        1. phopholipase C (PLC) works with phosphoinositide (PIT) to cleave (hydrolyze) membrane bound phosphatidyl inositol (POS) into inositol triphosphate (IP3) and diacylglycerol (DAG) (NOTE: lithium blocks this); IP3 binds to a receptor on the endoplasmic reticulum releasing Ca to bind to various Ca binding proteins; DAG activates protein kinase C (PKC) (with Ca as a cofactor) which then phosphorylates ion channels to increase Na and decrease K conduction causing depolarization
        2. Protein kinase A – NE binds to its receptor and activates a G-protein that activates adenylate cyclase to catalyze cAMP from ATP; cAMP activates protein kinase A (PKA) that phosphorylates a K channel reducing its permeability and depolarizing the neuron
          1. cAMP is degraded by cyclic nucleotide phosphodiesterase that is controlled by the concentration of calcium; balance of activation by adenylate cyclase and degredation by cyclic nucleotide phosphodiesterase is tightly controlled – increases in cAMP last only a few minutes at most
          2. Remember: PKA is linked with cAMP
        3. Eicosanoids – metabolites of arachidonic acid that are synthesized via G-protein activated phospholipase A2 or PLC; eicosanoids act as intracellular second messengers and as agents that leave the cell to act as first messengers to nearby cells; eicosanoid include leukotrienes and prostaglandins
    2. Ca mediated second messenger cascades – Ca ions can enter neurons and alter transmembrane voltage but act primarily as a second messenger
      1. Ca either enters through voltage gated or ligand gated channels or is released intracellularly from endoplasmic reticulum stores by inositol triphosphate (IP3); intracellular free Ca is low due to many binding proteins
      2. Ca has direct actions by itself and acts through Ca binding protein intermediaries such as calmodulin; calcium/calmodulin activate protein kinases that phosphorylate K channels reducing its permeability and depolarizing the cell
      3. Ca is removed from the cytosol following an action potential by active transport, binding to cytosolic proteins or transport into intracellular Ca storage vesicles
    3. Enzyme actions
      1. Kinases and phosphatases are important enzymes; kinases phosphorylate and phosphatase dephosphorylate channels that change their permeability to ions or affinity for binding ligands
      2. One class of kinases/phosphatases are tyrosine kinases. Tyrosine kinases are transmembrane enzymes with their regulatory domains exposed to the extracellular compartment where they act as receptors for their cytokine ligands. Upon ligand binding the tyrosine receptor kinases are internalized, form dimers, are autophosphorylated and are translocated to the nucleus where they participate in the regulation of gene expression. Some of the most important cytokines for neurons are the neurotrophins, the most familiar of which is nerve growth factor (NGF)
      3. Other enzymes may alter the activity of genes such as c-fos and c-jun through second messengers which have transcription factors (c-fos may direct synthesis of a new protein to make a new channel for example)
  8. Neuropharmacology
    1. Acetylcholine
      1. Synthesized from acetyl CoA + choline in the presence of the enzyme choline acetyltransferase
        1. Rate limiting step is the uptake of choline into the cell
      2. Degraded by acetylcholinesterase to choline and acetate
        1. Unlike many other transmitters, ACh is not returned intact to the presynaptic terminal by reuptake and thus the main means of terminating ACh action is by acetylcholinesterase
        2. Action of ACh may be extended by blocking degredation of ACh with physostigmine which inhibits acetychlinesterase
        3. Hemicholinium interferes with acetylcholine synthesis and therefore has an anticholinergic effect; Remember: ‘hemi’cholinium keeps ACh in ‘halves’
      3. Present throughout the CNS and at the neuromuscular junction
        1. High concentration at the nucleus basalis of Meynert and diagonal band of Broca structure which are implicated in the development of Alzheimer’s
          1. diagonal band of Broca is the medial border of the anterior perforated substance and contains amygdaloseptal and septoamygdalar fibers; nucleus of the diagnonal band projects via the fornix to the hippocampal formation
      4. Receptors – two major classes
        1. Nicotinic
          1. ligand gated with 5 subunits – 2 alpha, 1 each of beta, gamma and delta; the binding site is on the alpha subunit so each nicotinic ACh receptor can bind two molecules of ACh; alpha unit contains four hydrophobic transmembrane portions (Remember: 5’4”)
          2. the transmembrane segment is the most highly conserved and the cytoplasmic loop is least highly conserved
          3. opens cation channels (Na, K or Ca)
          4. blocked by curare, hexamethonium, botulinin
            1. alpha-bungarotoxin (snake venom) blocks nicotinic ACh receptor irreversibly
            2. beta-bungarotoxin (black widow spider) causes release of ACh from nerve terminals and depeletes stores
            3. curare blocks nicotinic ACh receptor channel reversibly (similar to the way that atropine blocks the parasympathetic neuroeffector junction)
            4. botulinin – blocks ACh vesicle release
            5. hexamethonium blocks receptor at the autonomic ganglia
        2. Muscarinic
          1. G-protein coupled to ion channel
          2. may open or close K, Ca or Cl channels
          3. agonists: pilocarpine (acts post-synaptically)
          4. blocked by: atropine, scopolamine
            1. scopolamine has good CNS penetration
      5. Role in autonomic nervous system
        1. Parasympathetic – preganglionic use nicotinic, postganglionic use muscarinic
        2. Sympathetic – preganglionic uses nicotinic, postganglionic uses NE on alpha and beta receptors
        3. Unlike ACh receptors at the neuromuscular junction, ACh receptors in the autonomic ganglia contain only 2 types of subunits; fast EPSP is mediated by nicotinic ACh receptors, the slow EPSP is mediated by muscarinic receptors opening Na and Ca channels and closing K channels while the slow IPSP is mediated by muscarinic receptors that open K channels
    2. Serotonin
      1. Contains an indole nucleus; synthesized from tryptophan by tryptophan hydroxylase (rate limiting) eventually into 5–HT; inactivated by monoamine oxidase (MAO)
        1. 5-HTP is converted to 5-HT by L-aromatic amino acid decarboxylase which also converts dopa to dopamine
      2. Dorsal raphe nuclei which surrounds the aqueduct in the dorsal midbrain contains many serotonergic neurons that project widely; serotonergic neurons are found only in the raphe nuclei of the brainstem
      3. Action may be both excitatory and inhibitory depending on the receptor
      4. All serotonin receptors have a G-protein coupled neuromodulatory and ion channel actions
      5. Reserpine depletes vesicular serotonin; the street drug XTC promotes release and blocks reuptake; LSD and buspirone are serotonin agonists as well (LSD stimulates serotonin receptors); imipramine, amitryptyline and prozac inhibit reuptake
      6. Decreased serotonin is associated with depression and migraine; excess serotonin and NE is associated with mania
    3. Amino acid transmitters – glutamate and aspartate (excitatory), GABA and glycine (inhibitory)
      1. Glutamate and GABA are found virtually everywhere in the CNS; aspartate and glycine are found in the forebrain and spinal cord respectively
        1. Glutamic acid decarboxylase is utilized in the synthesis of GABA
      2. Receptors
        1. Glutamate and aspartate (excitatory) – 4 types (AMPA, Kainate, NMDA, metabotropic) – all are ligand gated and permeable to monovalent cations
          1. ligand gated AMPA and Kainate receptors gate Na/K channels and are the most ubiquitous
            1. AMPA is an ionotropic glutamate receptor involved in fast excitatory synaptic transmission; Remember: AMPed up receptors move quickly
            2. Kainate is a slower receptor
          2. ligand and voltage gated NMDA receptor (only one of the 4 that is voltage gated) (blocked by Mg which can be displaced by activation) gates Na, K, and Ca into the cell (only one of the 4 that is permeable to Ca); NMDA receptor is involved in long-term potentiation and depression and is thought to be important in learning and memory
            1. NMDA receptors are unique in that they require simultaneous binding of two different agonists for activation (e.g. glutamate and glycine)
            2. excessive glutamate activity overactivates the NMDA receptor resulting in the gating of toxic levels of Ca and subsequent excitotoxic cell death; NMDA antagonists may play a protective role in ischemic stroke or head injury
            3. phencyclidine (PCP) is an NMDA receptor blocker but causes schizophrenic like symptoms
          3. metabolic glutamate receptor is a G protein receptor that releases Ca from endoplasmic reticulum and activates protein kinase C
          4. (NOTE: Huntington’s disease can be mimicked pathologically by injection of quinolinate, a glutamate receptor agonist)
        2. GABA – two types: A and B; both inhibitory
          1. GABAa is ligand gated with modulatory binding sites for benzodiazepines and barbiturates; opens a Cl channel and is blocked by picrotoxin
          2. GABAb is a G protein receptor coupled to ion channels; open K/close Ca channels; binding site for baclofen
          3. GABAergic degredation implicated in Huntington’s disease and seizures
          4. Blockade of GABA receptors may cause distortion of visual evoked responses
        3. Glycine – works via strychnine sensitive (i.e. strychnine blocks glycine receptors) Cl conductance; glycine is found mostly in the spinal cord but is also present in the brain – GABA and glycine are naturally excluded by the blood brain barrier and require mediated transport to get across
        4. NOTE: whether a synaptic potential is excitatory or inhibitory is determined not by the type of transmitter released from the presynaptic neuron but by the type of ion channels gated by the transmitter in the postsynaptic cell; nonetheless some transmitters act predominantly on receptors that are of one or another sign such as glutamate that typically produces excitation and GABA or glycine that produces inhibition
        5. The morphology of excitatory and inhibitory neurons can sometimes be distinguished by morphology; excitatory (Gray type I) neurons have a larger active zone and wide synaptic cleft while inhibitory (Gray type II) neurons have small active zones and a narrow synaptic cleft
      3. Dopamine
        1. Synthesized from tyrosine in the presence of tyrosine hydroxylase (rate limiting) to L-DOPA which is converted to dopamine in the presence of DOPA decarboxylase. Dopamine and NE are in the same biosynthetic pathway
        2. Degraded by monoamine oxidase with main metabolite being homovanillic acid (blocking monoamine oxidase will increase the amount of dopamine)
        3. Nigrostriatal system is major source of CNS dopamine; also present in adrenal medulla
        4. Five major types of DA receptors; D1/D5 postsynaptic, G protein modulated in striatum and cortex; D2 presynaptic in striatum
        5. D1 stimulates cAMP and increases PIP2 hydrolysis; D2 inhibits cAMP (increases K/decreases Ca conductance)
          1. D1 receptors are in the striatum and neocortex
          2. D2 receptors are in the striatum, substantia nigra and pituitary; activation of D2 receptors decreases the release of transmitter at the synaptic terminal
          3. D3 receptors are in the olfactory tubercle, nucleus accumbens and hypothalamus
          4. D4 receptors are in the frontal cortex, medulla and midbrain; blocked by clozapine preferentially leading to the treatment of psychosis without the extrapyramidal effects of most antipsychotics
          5. D5 receptors are in the hippocampus and hypothalamus
        6. Blocked by haloperidol, clozapine; agonist – bromocriptine; reuptake blocked by cocaine, amphetamine; reuptake facilitated by lithium; antipsychotics primarily block D2 receptors (excess dopamine is associated with hyperkinetic movement disorders and can be brought on by cocaine or amphetamine abuse); these side effects can be treated with anticholinergic drugs such as trihexyphenidyl (Artane)
          1. in a very simplistic view, the cholinergic and dopaminergic systems have antagonistic actions and must be balanced
        7. Schizophrenia is thought to be caused by an overstimulative state of dopamine
      4. Norepinepherine
        1. Synthesized when dopamine is in the presence of dopmine-B-oxidase – thus drugs that affect dopamine also affect NE
          1. norepinpherine is the precursor of epinephrine
          2. overall synthesis: phenylalanine to tyrosine, tyrosine to dopa, dopa to dopamine, dopamine to norepinepherine, norepinepherine to epinepherine
        2. Degraded by monoamine oxidase (e.g. catechol-o-methyltransferase) but main means of termination of action is by reuptake into the presynaptic terminal
        3. NE containing neurons from the locus ceruleus in the dorsal pons project to the cortex, limbic systems, reticular activating system (RAS) and cord
        4. Receptors are of two types: pre- and post-synaptic; both are G-protein linked to activity of cAMP which causes an influx of Ca
        5. Agonists: isoproterenol (beta) and clonidine (alpha)
          1. isoproterenol is a potent nonselective beta adrenergic agonist with very low affinity for alpha adrenergic receptors; lowers peripheral vascular resistance, diastolic pressure falls and cardiac output is increased because of the positive inotropic and chronotropic effects of the drug in the face of diminished peripheral vascular resistance; relaxes all varieties of smooth muscle and relieves bronchoconstriction; Remember: ISOproterenol is ISOlated on beta receptors
        6. Antagonists: propranolol (beta) and yohimbine (alpha)
      5. Neuropeptides – four classes: pituitary hormones, hypothalamic releasing hormones, gut-brain peptides and opioid peptides; peptides can only be synthesized in the cell body as opposed to the monoamines that can be formed in all parts of the neuron; peptides are typically cleaved from larger molecules (called prohormones); most monoamines are contained in the brainstem while peptides are spread over brainstem, forebrain and the limbic system; peptides are also found in the sympathetic ganglia and act as neuromodulators rather than neurotransmitters
        1. Pituitary – ACTH, vasopressin, oxytocin, alpha-MSH
          1. precursor of ACTH/endorphin/MSH/lipotropin is pro-opiomelanocortin (POMC) that may also have some neurotransmitter effects
            1. beta-endorphin and MSH are contained in beta-lipotropin
        2. Hypothalamic – somatostatin, LHRH, TRH
        3. Gut-brain: CCK, VIP, substance P (neuropeptides NOT neurotransmitters)
        4. Opioid – Beta-endorphin, met-enkephalin, leu-enkephalin
          1. opioid peptides endorphin and enkephalin bind to opiate receptors in the substantia gelatinosa and periaqueductal grey to produce analgesia; morphine does similar thing
          2. morphine binds to opioid mu receptor; mu receptor causes release of histamine from neurons which is thought to play a role in the relief of pain
          3. morphine and related alkaloids also produce postsynaptic inhibition of glycine responses
          4. morphine causes nausea by binding to chemoreceptors in the area postrema of the medulla
          5. opioid withdrawal manifests with mydriasis and anxiety
        5. Most have multiple roles and trigger complex events; enkephalin is widely distributed in the brain and spinal cord and is found in high concentrations in the pituitary; enkephalin receptor stimulation provides short lived analgesia in comparison to endorphin mediated analgesia which provides relief for hours; enkephalins have an antidiuretic effect
        6. many peptides co-released with neurotransmitters
          1. ACh with VIP
          2. NE with somatostatin or enkephalin
            1. Somatostatin is found in the dorsal root ganglia and the anterior hypothalamus; somatostatin concentration in the neocortex and hippocampus is reduced in patients with Alzheimer’s disease
            2. Somatostatin regulates the release of GH and TSH from the hypophysis
          3. Dopamine with CCK or enkephalin
          4. serotonin with substance P or TRH
            1. substance P is a powerful excitatory neurotransmitter that is found in the raphe nucleus (in addition to serotonin), caudate and putamen, spinal trigeminal tract, and dorsal root ganglion cells
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