L4: Synapses&neurotransmitters

Types of neurones: motor neurones, pyramidal neurone (hippocampus), purkinje neurone (cerebellum)

Synaptic Trasmission (chemical): e.g. neuromuscular junction (synapse between motor neurones&skeletal muscle)

neurotrasmitters are released resting neuromuscular junction
voltage gated Ca++ channel: open in response to changes in membr. depolarisation

ACheR=> ligand gated ion channels, non-specific cation channels

vesicles containing neurotransmitter (ACh)

activated neuromuscular junction:

1) AP generated <>

2) depolarisation

3) open Ca++ cause: Ca++ entry to presynaptic

4) cause ACh vesicles fuse with membr. to release ACh in synapse

5) let Na+ ion generates local potential /AP

6) when open -->> muscle-->>contraction

7)in skeletal muscle Ca++ release=>contraction

Neurotransmitters:

a.a.=>γ-aminobutyric acid (GABA), Glutamate, Glycine

amines=>ACh, Dopamine, Histidine, Noradrenaline, 5-HT (Hydroxytryptamine)

peptides=> Cholecystokinin, Dynorphin, Enkephalins, Neuropeptide Y, Somatostatic

gases=> NO, (CO)

Criteria for Identifying neurotransmitter:

1) Localisation

2) Synthetic/catabolic mechanisms: occurs in dif.ways

• Neurotr. synthesis:e.g. peptide neuron/DNA protein (all body), RER, Golgi apparatus, vesicle, transported in axon terminal, synaptic vesicles nerve terminal



• synthesis&degradation of ACh: catalyses synthesis ACh transporter=>

ChAT(cholic acetyl transferase)--> formation of Ach<Ch+Ac.CoA

AChE (acetyl choline esterase) breakdown ACh-->> acetic acid+choline (recycled for synthesis of ACh)

Ach=> package up inside vesicle to be trnsferred release<>

3)Release from terminal

release of neurotransmitter (e.g. ACh)by exocytosis: synaptic vesicle: protein-protein interactions binding to membr., once membrane depolarised, entry Ca++ allows vesicles to release content, neurotrasmitter molecules molecules : vesicle pinches back to presynaptic.

neurotransmitter receptors:

• ACh: ligand-gated ion channel=> ionotropic receptors: allow movements of ions: 1) signal proteins open, 2)allow ions in, 3) causes hyperpolarisation/depolarisation


• G-protein-coupled receptors => metabotropic: reflecting much slower on cellular metabolism, more time consuming process

Active G: activate ions->change in excitability-> cellular effects

Active G: activate E-> cause 2nd msg->Ca++ release/protein phosphorylation

4) Synaptic mimicry->stimulate nerve

5) Pharmacological identity of action: block effect of suspected neurotr. in the same way of directly stimulating nerves

Synapses in the CNS:

1) Variety-Types of synapses in the CNS:

2)Size &Shape of CNS synapses:

• presynaptic terminals contain vesicles arranged @ active zones => RELEASE
• postsynaptic membr.=> specialized&contains clusters of neurotransmitters receptor&signalling molecules

3) Excitatory/inhibitory synapses:

e.g. glutamate generates excitatory post synaptic potential (EPSP) Na+ entry causes local/ small depolarisation

/ e.g. γ-aminobutyric acid generates inbitory post synapric potential (IPSP) entry to cell more (-) inside cell, hypepolarisation

4)Synaptic integration:

temporal summation: adding 2gether local potentials that occur @ same synapse, but dif. times

spatial summation: adding 2gether local potentials that occur @ dif. sites on neurone=> more often cuase loc. potentials dont travel v. far

5)Electrical synapses: --> gap junctions: brain&heart

apart<>

formed<>

elec. synapses affect integration: generate elec. pot. although no enzyme released: If record Vm of cell 1 and cell 2 elect. PSP

lower curve than AP @ same time

6) network of neurones: convergence/ divergence

L3: Action Potential and conduction

Structure of ion channels:

• K channels: 4 subunits (transmembrane domain) proteins arranged in a barrel to form a pore htat spans the membr, are selective for K+ cuase of polypeptide sequence lines the pores of the ion

• Sodium Channels: single (only 1) subunit made up of 4 times repeating 6transmembr. segments, have pore-lining region-->> determines selectivity, lets Na+ pass through, contain voltage sensing domain rotate&moves up causing pore to open by conformational change!
  
  

Activation State of ion Channels
3 states of conformational change:

• resting state: closed- no ion flow
• activated state: open-ion flow (Na+ influx)
• inactivated state: closed-no ion flow :

*Refractory period: Na+channels become inactivated as the membr. depolarizes and cannot be activated again until the membr. is repolarized.

membr. hyperpolarized until K+ channels close, so more current required to depolarize membr. potential to more positive

• absolute refractory period: when during AP a 2nd stimulus no matter how strong will not produce a 2nd AP, inactivated closed channels
• relative refractory perod: can last 1-15ms, coincides with after hyperpolarisation, interval during which 2nd AP can be produced ONLY if stimulus strength = greater than treshold.

Action Potential/ Spike/Nerve impulse discharge:

rapid large alterations in membr. potential up to 100mV from -70 to +30mV, inside cell becomes more (+)!
Only EXCITABLE (nerve, muscle, endocrine, immune, reproductive) CELLS produce AP

≠ ALL CELLS can produce local potentials

Threshold: point where all Na+ channels open
Overshoot: always go above OmV~ENa+
All or nothing event: once pass threshold always generate this size of potentia, Always get same height, amplitude in graph every cell same Na channels=>same size eq.,
Refractory period:*
Propagate: act of ion potential
No decrement
undershoot: ~EKa+

Conduction velocity: propagation/A.P. conduction, A.P. travels down axon, no backwards cause absolute refractory period inactivated closed channels, SIGNAL<>> MUSCLES

Myelin: ↑diameter of axon, ↑myelin (stimulating substance, round axon, insulation to speed up flow of AP membr.)=> better, faster AP

Nodes of Ranvier (Saltatory=jumping conduction:

node/gaps in myelin, clusters of Na+ channels

Local Potentials: confined to a small region of cell membr., small response,

size: vary,

dicited. stimuli

dif.names depending on location/function

depolarization/hyperpolarization

graded-size/duration

decay rapidly,

travel small distances

show summation

e.g. endplate, synapric, pacemaker, receptor potential

polarized: outside/inside cell=> dif. net charge

depolarized: potential ↓ (-) than resting potential level (Na+ influx)

overshoot: reversal of membrane potential polarity, inside of cell becomes (+) relative to outside

repolarizing: when a membr. potential that has been depolarized returns toward the resting value (K+ Efflux)

hyperpolarized: when potential is more (-) than restin lvl

undershoot: E~K+ r.m.p.

Graded potentials (cause magnitude of potential change can vary): changes in membrane potential that are confined to a relatively small region of the plasma membr. produced < some specific change in cells environment acting on a specialized region of membr. they are given various names related to location of potential/function perform.

L2: MEMBRANE POTENTIAL

Equilibrium potential
Nerst eqn: E=60logCo/Ci (mV)
Eq.pot. for a particular ion, [ion] out/in, 60: constant taking into account: R, T, valance of ion, Faraday elec. constant
If [ ] changes =>E changes
E for K+ ~-80mV, Na+ ~ +60mV

Ion movements once s.s. has been achieved:although few open Na+, Na+ larger e-chemical force acting upon it, that is, it is far <>> ↑ membr. permeability -->> ion species-->> ↑ contribution of ion species to membr. potential

Resting membrane potential =-70mV*
Goldman eqn: Vm=60log (PK[K]o+PNa[Na]o+PCl[Cl]i)/PK[K]i+PNa[Na]i+PCl[Cl]o)2.303RT/F=60Pion-->> relative permeability of ion
K+=1, Na+=0.035, Cl-=0.001 (more permeable to K+ because for K + channels found on those membranes <>
*neither Na+, nor K+=> Epotential, but r.m.p. is closer to K+ Epotential, because membr. more permeable to K+
K+ moves out through open leak K+ channels
inside cells becomes (-)K+flux has more import on r.m.p. than Na+ flux,
but Na+ (small no) channels also open in resting state
Na+move in cell, cancelling effect on equivalent no of K+ions simultaneously moving out.
there is a NET movement <>
Over time, [ ] of intracellular Na+, K+ ions does not change because Na+K+ATPase pump maintains&helps to establish [Na+, K+] gradients @ stable lvls, as they move 3Na+ out & 2K+ in.
This unequal transfer contributes directly to membr. potential.

Note: In a resting cell, the no of ions that move in the opposite direction through membr. channels down their [ ] and/or elec. gradients. As long as the [ ] gradients remain stable and ion permeabilities of the plasma membr. do not change, elec. potential across the resting membr. will also remain constant.

Excitable cell
Neurones, muscle cells, grandular tissue, fertilised eggs, plant cells-->>RMP
Express correct ion channels: VOLTAGE GATED ION CHANNELS

Different types of ion channels (sensory system: mechanosensitive ion channes, phosphorylation sensitive ion channels, poring for H2O channels. 2 of the most characteristics:)

• Ligand-gated ion channels: (e.g. ACh Receptor) change from close to open, protein shape change to open
• Voltage-gated ion channels: passive down elec.gradient, rapid, important for signalling in nervous system, cation channels, relatively selective for: K+, Na+, Ca++(40/40-12/12dif.channels)/ anion channels: realtively selective for Cl-

proteins exist in open, inactivated, closed states depending on membrane depolarization.

change in charge induces change!

L1: CELL MEMBRANE&SOLUTE MOVEMENT

Body Fluid Compartments:
70kg person (x 60% or 2/3 body weight H2O) 42L H2O:

• 2/3 inside cells
• 1/3 outside cells : 20% plasma, 80%between cells

Stable composition: functional consequnces of the [ ] gradients on nerve cells:

• IN: HIGH: K+, LOW: Na+, Cl-, Ca++ (really low)
• OUT: LOW: K+, HIGH: Na+, Cl-, Ca++ (acts as a signalling molecule-->>important how muscles contract: CARDIAC)

Cell membrane function:

boundaries cellular components within cell, cells&environment, specialised for functions they perform, selective permeability

larger/charged molecules,need proteins--small/uncharged/polar molecules,no proteins, pass easily

Na+, K+, Cl-, glu/tryptophan, urea, glycerol, H2O/alcohols

LOW permeability HIGH permeability

Passive Transport

Diffusion: flow of particles (O2, CO2) <>> areas of ↓ [ ]

dependent on 1) [ ]gradients (may require E to establish them)

2) passive process/membrane impermeable to glu: proteins r required

Simple Diffusion: membrane, Osmosis (↑ H2O/ ↓osmolatiry-->> ↑osmolairty ↓H2O): porins,

Facilitated diffusion: transporters: carriers=integral membr. proteins where solutes bind changing shape protein&solute released on the other side of membrane down gradient

diffusion rate determined<>> ethanol ↑ permeability

NET FLUX

Active transport pumps (carriers) against gradient, requires ATP

direct use (HYDROLYSIS) of ATP-->>ADP+Pi: Primary active transport: from α subunit of Na+K+ATPase 3Na+ out, 2K+ in

Secondary active transport: nutrient absorption in gut oupled to Na+ transport