Chapter 13

Front 1

synapse

Back 1

- specialized site of contact of a neuron with another neuron or an effector
- locus = where one cell influences function of another
- synaptic cleft = space separating neurons

Front 2

2 synaptic functions

Back 2

- synaptic transmission
- synaptic plasticity

Front 3

synaptic transmission

Back 3

- site where presynaptic signal has an effect on a postsynaptic cell
- usually chemical but can be electrical
- excite or inhibit postsynaptic cells

Front 4

chemical synapse

Back 4

- cells not connected
- relay on diffusion of NT
- unidirectional
- discontinuity between cells
- synaptic cleft barrier to direct electrical communication
- presynaptic releases NT that rapidly diffuse to postsynaptic where they bind to receptor molecules that generate electrical or chemical change
- excitatory or inhibitory = depend of type of NT and receptor
- high level plasticity = important for development and learning
- amplify current flow = depends on amount of NT released and number of receptors on postsynaptic

Front 5

electrical synapse

Back 5

- electric currents from one cell flow directly into next cell, changing membrane potential
- connected by gap junction
- fast synaptic transmission
- not polarized = bidirectional
- synchronizing ability

Front 6

synaptic plasticity

Back 6

- ability to change functional properties of synapses

Front 7

gap junction

Back 7

- low resistance pathways to allow current to flow
- specialized locus where protein channels bridge the gap between 2 cells, directly connecting cytoplasm
- electrical synapse
- electrical coupling
- differ in strength = larger it is, stronger the coupling
- connexons of 2 adjacent membranes

Front 8

connexons

Back 8

- regular array of channel structures
- composed of hexamors of the protein cannexin
- hemichannels = connexons join together to form channels
- low resistance pathways
- can close in response to electrical or chemical changes

Front 9

electrocytes

Back 9

- modified muscle cells that lost capacity to contract
- produce about 10V to 15V
- stacked in electric organ
- nicotinic acetylcholine receptors
- compared to voltaic pile

Front 10

synaptic vesicles

Back 10

- stores neurotransmitters

Front 11

active zones

Back 11

- dark tufts of electron dense material on cytoplasmic side of presynaptic where synaptic vesicles release their NT

Front 12

postsynaptic densities

Back 12

- reflect accumulation of NT receptors and scaffolding proteins

Front 13

scaffolding proteins

Back 13

- help organize receptors and other proteins at synpase

Front 14

NT receptors

Back 14

- transmembrane receptors
- work in one of two ways = ionotropic, metabotropic

Front 15

ionotropic

Back 15

- chemical synapse
- movement of ions to generate action potential
- binding of ion transmitter opens ion channel
- much quicker
- produce fast changes in membrane potential by directly increasing permeability to ions

Front 16

metabotropic

Back 16

- trigger signaling cascade of second messengers in post synaptic cell
- relatively slow
- long lasting modulatory effects

Front 17

synaptic potential

Back 17

- transitory, graded change in resting membrane potential
- control neuronal excitability
- neural integration
- neurons output determined by sum of all neuronal inputs
- depolarizes = excitatory postsynaptic potential (EPSP)
- hyperpolarizes = inhibitory postsynaptic potential (IPSP)

Front 18

excitatory postsynaptic potential

Back 18

- rising phase and exponential decay
- temporal summation = resultant EPSP of peripheral nerve A stimulated repeatedly and rapidly
- spatial summation = combination of simultaneously occurring EPSP produced by different nerves
- smaller postsynaptic membrane at synapse smaller
- presynaptic membrane release less NT
- in CNS most common NT is glutamate

Front 19

inhibitory postsynaptic potential

Back 19

- drive membrane potential away from threshold
- produce temporal or spatial summation

Front 20

neuronal integration

Back 20

- neuron's output
- spatial and temporal summation of EPSP and IPSP
- spatial = many fibers converge on single postsynaptic
- summation = waves of transmitter release

Front 21

functional chemical synapse

Back 21

- action potential arrives at terminal buton
- opening of voltage gated Ca channels
- binding to ionotropic receptors
- binding to metabolic G protein coupled receptors

Front 22

fast chemical synapses

Back 22

- workhorse of synaptic mechanism
- neuromuscular junction = model system for chemical synaptic transmission
- functions as relay synapse
- anatomical simplicity
- large synaptic response
- summary of events in chemical synaptic transmission

Front 23

fast IPSP

Back 23

- hyperpolarizing
- increase in permeability to Cl ions
- mediated by GABA and glycine
- NT usually

Front 24

chemical synaptic transmission

Back 24

- action potential depolarized presynaptic terminal and opens voltage gated Ca channels
- Ca enter
- triggers release ACh to synaptic cleft
- NT bind to specific receptor proteins
- ligand-gated channels open, allowing ion flow = produce EPSP that spreads decremental
- depolarize muscle fiber membrane to threshold and initiate a muscle fiber action potential
- action of NT terminated by enzymatic degradation or by reuptake
- choline transporter retrieves choline into presynaptic terminal for ACh resynthesis

Front 25

acetylcholinesterase

Back 25

- enzyme synthesized by postsynaptic muscle fibers and located in synaptic cleft
- destroys ACh

Front 26

during EPSP

Back 26

- Na and K increase simultaneously
- synaptic current = produces depolarization that is the rising phase of an EPSP
- drive membrane toward a potential near zero

Front 27

aceytlcholine

Back 27

- synthesized from choline and acetyl choline A
- ACh taken up into vesicles
- docked or anchored

Front 28

NT release

Back 28

- stimulus = depolarization
- amount released increase with depolarization
- dependent on influx of Ca ions

Front 29

Ca has 3 effects

Back 29

- binds to calmodulin
- binds synaptobrevin/synaptophysin complex
- another protein in syaptotagmin binds to Ca at high concentrations

Front 30

Ca binds to calmodulin

Back 30

- complex activates calmodulin-dependent protein kinase which is a tyrosine kinase
- hydrolyzes ATP
- synapsin 1 + P disrupt interaction with actin
- vesicles released

Front 31

binds synaptobrevin/synaptophysin complex

Back 31

- synaptobrevin is V snare that binds to congate T snare
- V and T snares are docking proteins

Front 32

another protein in syaptotamin binds Ca at high concentrations

Back 32

- synaptotagmin 1 = integral membrane glycoprotein
- functions as calcium sensor to synchronize NT release
- calcium dependent exocytosis activator protein

Front 33

clastoidal bacteria

Back 33

- associated with botulism and tetanus
- secrete protease that serve as neurotoxins to break down snares

Front 34

vesicular docking and fusion

Back 34

- release NT
- targeting = vesicles move to active zone
- docking = V and T SNAREs bind, vesicle irreversibly docked
- Ca entry = Ca binds to synaptotagmin
- fusion = synaptogmin triggers membrane fusion and exocytosis

Front 35

vesicle recycling

Back 35

- allows synaptic vesicles to reform and prevents plasma membrane from expanding
- synaptic vesicles are mobilized or targeted to move to release sites
- dock and are primed until Ca trigger fusion
- endocytosis = a pinching off from terminal membrance

Front 36

membrane retrieval/vesicle recycling

Back 36

- NT released into the cleft
- clathrin helps selectively retrieve vesicular membranes along with dynamin
- adaptin interacts with clathrin
- dynamin promotes reuptake of vesicles
- some require ATP

Front 37

2 modes of fusion

Back 37

- classical
- kiss and run

Front 38

classical

Back 38

- vesicular membrane merges with terminal membrane and new vesicle is later retrieved by endocytosis
- selectively retrieves vesicular membranes
- two proteins aid: clathrin and dynamin

Front 39

kiss and run

Back 39

- docked vesicles opens a fusion pore to release transmitter into synpatic cleft without becoming completely integrated
- faster and may predominate at lower rates of release

Front 40

proteins in vesicle release

Back 40

- synapsin attaches vesicle to actin cytoskeleton and released when phosphorylated
- SNAREs
- Munc18 and complexion prime docked vesicles
- synaptotagmin = Ca bind to trigger formation of a fusion pore that may lead to exocytotic fusion
- rab 3 is active in vascular mobilization and recycling and may inhibit excessive fusion and release
- cytoplasmic proteins may disassemble SNARE

Front 41

SNARE proteins

Back 41

- mediate fusion of cellular transport vesicles
- vesicles (v SNARE)
- target (t SNARE)

Front 42

3 SNARES

Back 42

- syntaxin 1, SNAP-25 in cell membrane and synaptobrevin in vesicular membrane
- syntaxin and synaptobrevin anchored by C-terminal domains
- SNAP-25 tethered via cysteine-linked palmitoyl chains
- 4-alpha-helix bundle = 1 for syntaxin 1, 1 for synaptobrevin, 2 for SNAP-25

Front 43

t SNARE

Back 43

- target
- located in membranes of target compartments
- hold docked vesicle at active zone
- syntaxin and SNAP

Front 44

v SNARE

Back 44

- vesicular
- incorporated into membrane of transport vesicle
- intertwine with terminal membrane
- syaptobrevin

Front 45

postsynaptic potentials

Back 45

- spread decrementally because they don't result from action of voltage gated channels
- ACh receptor = ligand gated Na-K channel
- no current flow = NT open channels

Front 46

metabotrophic synapse action

Back 46

- doesn't directly open ion channels
- 7 transmembrane segments in receptors
- G protein coupled receptor
- binding of NT to GCPR cause conformation change
- alpha subunit release GDP and binds GTP = becomes activated
- alpha subunit binds to adenyl cyclase = change ATP to cAMP
- cAMP activates protein kinase which releases catalytic
- GTP can also bind to some kind of channel or intracellular effector

Front 47

synaptic delay

Back 47

- neurons can transmit action potential at 150m/s
- neuronal transmission across synapses is slower time to open Ca channels, release NT, diffusion across cleft, binding receptor, change postsynaptic
- rate limiting step

Front 48

2 major kinds of NT

Back 48

- small-molecule NT = amines and amino acids
- neuropeptides

Front 49

amino acid

Back 49

- most synapses use
- most fast EPSP = glutamata
- most fast IPSP = GABA or glycine

Front 50

biogenic amine

Back 50

- found in relatively few neurons
- slow actions that modulate neural activity
- contain amine with a calcite group benzene ring with 2 adjacent hydroxyl groups
- synthesis starts with amino acid phenylalatine

Front 51

peptide

Back 51

- chains of amino acids
- synthesized in cell body of neuron
- propeptide = large precursor polypeptide
- large dense-cored vesicles = contain propeptide molecules
- exocytosis of large dense-cored vesicles not at active zone
- digested by nonspecific extracellular peptidases
- locally retrieved or rapidly resynthesized = resupply
- present the least
- co-released
- may regulate transmission of pain information
- presynaptic inhibition of enkephalin (peptide) decreases the amount of NT release from the second neuron
- enkephalin decreases synaptic transmission

Front 52

multiple receptors

Back 52

- different postsynaptic actions at different postsynaptic cells
- ACh excites skeletal muscle via EPSP but inhibits cardiac muscle via hyperpolarizing IPSP
- ACh receptor of skeletal muscle = nicotine
- ACh receptor of heart muscle = muscarinic

Front 53

termination of NT action

Back 53

- enzymatic destruction
- reuptake

Front 54

enzymatic destruction

Back 54

- acetylcholinesterase (AChE) = terminates the postsynaptic effects of ACh and provides choline

Front 55

reuptake

Back 55

- norepinephrine
- Na entry down electrochemical gradient to drive transmitter uptake against concentration gradient
- actively transports molecules across membrane against concentration gradient

Front 56

acetylcholine

Back 56

- neuromuscular junction
- excitatory at neuromuscular junction
- nicotonic = iontropic
- muscarinic = metabotropic
- biogenic amine
- also in PNS and preganglia of autonomic system neurons and post ganglionic of parasympathetic

Front 57

choline acetyltransferase (ChAT)

Back 57

- synthesized within perikaryon
- transferred into terminal buton via axoplasmic flow or anterograde movement via kinesin
- makes ACh with choline and acetyl CoA
- choline rate limiting factor = supplied by blood with uptake transporters in presynaptic membrane

Front 58

ACh synthesis

Back 58

- in axon terminal
- acetyl CoA synthesized in mitochondria in terminal buton
- catalyzed by choline acetyltransferase

Front 59

ACh breakdown

Back 59

- taken into vesicles by specific vesicular transporters
- on vesicle membrane
- vesicular ACh transporter
- antiport with H+
- storage of ACh = quanta
- packaged with ATP
- ACh remains bound for brief period then released
- degraded by ACh esterase located on postsynaptic membrane and cleft
- choline recaptured by presynaptic membrane and reused

Front 60

botulism toxin and barbiturates

Back 60

- inhibit ACh release
- barbiturates act as CNS depressants
- decrease ACh levels in certain areas of Alzheimer patient's brain

Front 61

nicotonic receptors

Back 61

- found on motor end plates of skeletal muscle
- all sympathetic and parasympathetic ganglionic neurons
- hormone producing cells of adrenal medulla
- always excitatory
- nicotine causes rapid depolarization
- curate and some snake venoms block nicotonic R
- effects prolonged by nerve gas and organophosphate
- destroyed in myasthenia gravis
- ionotropic
- glucoproteins
- 5 transmembrane domains surrounded by ligand gated channel
- alpha domains bind ACh
- 4 membrane spanning regions: M1, M2, M3, M4
- M2 is polar and lines the channel
- conformational change in shape that opens the ion channel to allow Na and K flow
- inward Na larger than K outward
- creates EPSP
- prolonged exposure = inactivated or desensitized

Front 62

muscarionic receptors

Back 62

- parasympathetic targe cells, blood vessels in skeletal muscles, some sweat glands, heart
- mushroom alkaloid
- metabotrophic receptor
- R is inhibited by atropine
- simlatory and inhibitory
- ACh binding to cardiac muscle slows the heart
- ACh binding to smooth muscle in GI tract increases motility
- linked to G protein
- M2 domain activates G protein inhibitory protein that causes opening of K channels and depolarization lasting seconds, and decreases in contraction rate

Front 63

norepinephrine

Back 63

- biogenic amine
- metabotrophic
- excitatory or inhibitory depending of R type
- PNS = main transmitter of preganglionic cells of sympathetic nervous system
- CNS = brain stem, limbic system, some ares cerebral cortex
- good feeling NT
- release enhanced by amphetamines
- removal from synapse blocked by tricyclic antidepressants and cocaine

Front 64

norephinephrine synthesis

Back 64

- mostly in nerve terminal
- sotred in synaptic vesicles with ATP
- adrenergic nerve endings
- transported into synaptic vesicles by vesicular monoamine transporter
- VMAT integral membrane protein in vesicular membrane
- equal affinity for norephinephrine and epinephrine
- enzymatically inactivated by monoamine oxidase (MAO)

Front 65

monoamine oxidase (MAO)

Back 65

- removes amine group
- bound to outer membrane of mitochondria or synaptic cleft
- iron containing enzyme that exist as 2 isozymes A and B that have different affinities for various amines as substrates

Front 66

monoamine oxidase inhibitors (MAOI)

Back 66

- powerful antidepressant drugs
- used only when others fail

Front 67

- catechol-O-methyl transferase (COMT)

Back 67

- enzymatically inactivate norepinephrine
- methylation of 3-hydroxyl group of catechol ring
- postsynaptic membrane, synaptic cleft, pre-synaptic cell

Front 68

norepinephrine reuptake transporter

Back 68

- removes norepinephrine from synaptic cleft
- presynaptic membrane
- ATP used to drive transport
- amphetamines increase uptake

Front 69

2 major classes of NPR adrenergic receptors

Back 69

- both in 7 transmembrane domain receptor super family
- beta
- alpa

Front 70

beta

Back 70

- inhibitory
- G protein coupled receptor
- heart and coronary blood vessels, adipose tissue, vascular and airway smooth muscle

Front 71

alpha

Back 71

- activated by receptor occupancy
- stimulatory
- G protein coupled receptor
- blood vessels serving skin, pupils, and visceral organs, membrane of adrenegic axon terminals

Front 72

dopamine

Back 72

- biogenic amine
- excitatory or inhibitory depending on receptor
- midbrain and hypothalamus
- metabotrophic
- feel good NT
- reuptake blocked by cocaine
- deficient in Parkinson's disease
- maybe involved in schizophrenia

Front 73

seratonin

Back 73

- biogenic amine
- mainly inhibitory
- metabotrophic
- brain stem, midbrain, hypothalamus, limbic system, cerebellum, pineal gland, spinal cord
- play role in sleep, appetite, nausea, migraines, mood regulation
- prozac blocks reuptake and relieves anxiety and depression

Front 74

glumate

Back 74

- amino acid
- major excitatory NT of CNS
- ionotropic
- important in learning, memory, and motor control
- reuptake transporter in presynaptic membrane
- types: AMPA EPSP, NMDA Ca second messanger

Front 75

induction and maintenance of LTP

Back 75

- NMDA receptors blocked at resting potential by Mg ions
- receptors activated by drug N-methyl D asparate
- non NMDA receptors open to produce fast EPSP
- depolarization releases Mg
- Ca enters NMDA receptor channels and act as second messenger in cell activating Ca dependent protein kinase
- increase presynaptic NT release

Front 76

GABA

Back 76

- gamma amino butyric acid
- main inhibitory NT of brain
- GABA a = ionotrophic
* opens chloride channels IPSP
- GABA b = metabotrophic
* IPSP
- hypothalamus, purkinje cells, retina, and olfactory bulb
- inhibitory effect enhanced by alcohol and valium

Front 77

glycine

Back 77

- major inhibitory NT of spinal cord
- ionotrophic
- strychnine blocks receptor resulting in convulsions and respiratory arrest

Front 78

peptides

Back 78

- endorphines
- p substances

Front 79

endorphins

Back 79

- generally inhibitory
- metabotrophic
- wide spread in brain
- natural opiate
- inhibits pain by inhibiting substance p

Front 80

p substance

Back 80

- excitatory = mediates pain transduction in PNS
- metabotrophic
- dorsal root ganglia = pain affecters

Front 81

gases as NT

Back 81

- nitric oxide (NO) = ubiquitous signaling molecule
- involve in vasodilation, neurotransmission, immune response
- excitatory
- metabotrophic
- spinal cord, adrenal gland, nerves to penis
- release potentiates stroke damage

Front 82

NO produced by 3 iso-enxymes of NO synthase

Back 82

- endothelial nitric oxide synthase (eNOS) regulates vascular tone and smooth muscle tension
- neuronal nitric oxide synthase (nNOS) functions as a diffusible neurotransmitter
- cytokine inducible NO synthase (iNOS) acts as an effective defense mechanism during inflammation, but it also involved in arthritis and multiple sclerosis