B1/2 nervous excitation + synapses Flashcards
neuron functions
-excitable cells (able to modify their membrane potential) –> used for impulse generation and induction via ELECTRICAL CURRENTS (based on ion flow/distribution and ion channels)
-long distance communication and fast response generation (heart beat, muscle contraction)
Ion channel types
-allow ion flow thorugh membrane and dictate electrical behaviour
DIFF MECHANISMS OF CONTROL:
1. ligand gated
2. voltage gated
3. phosphorylation gated / signal transduction response
4. activated upon mechanical stimulus
structure of ion channels
TRANSMEMBRANE DOMAINS:
1. alpha subunit: main pore that the ions move through
2. beta subunit: communicating units attached distally
3. extra and intracellular loops joining the subunits (used in signal transduction)
Describe the kinetics and properties of ion channels:
PROPERTIES:
1. specific: to molecules they transport, molecules that stimulate them + direction they work in
- efficient: high rate of passage (higher than enzymes) bcos a very large flow of ions is needed to maintain/induce potentials
- controlled: closed or open gate depending on response necessary
KINETICS: open when activated and closed when inactivated, can be calculated using Patch clamp (isolating 1 channel in vitro and measuring kinetic capacities)
describe ligand gated channels
-activation controlled by a molecule (eg NTs)
-convert chemical signals into electrical
-show ion selectivity and transmisser specificity
3 families: nicotinic, glutamate and ATP ionotropic
2 mechanisms they work with: ionotropic and metabotropic
describe the 3 families of ion channels
- NICOTINIC: pentamers, contain sulfide bond between the 2 extracellular cysteine residues: used for Ach, serotonin, glycine, GABA
- GLUTAMATE: tetramers with extracellular ligand binding domains: used for glutamate
- ATP IONOTROPIC: trimers with both their C and N terminals on intracellular side (needs ATP to bind)
Describe the 2 mechanisms of ligand gated channels
- IONOTROPIC: fast(ms) and use ion flow
- METABOTROPIC: slow and use secondary messengers or signalling cascades
voltage gated channels description
-controlled by magnitude of membrane potential
-provide electrical stimulation for nerves and muscles
-4 transmembrane polypeptide units arranged around central pore
-can be Na+, K+, Ca2+
!!! Na channels phosphorylation promotes CLOSED config. (along with other factors for inflammation and toxins like pufferfish)
How is resting potential across the membrane maintained
-dynamic equilibrium of K+ and Na+ flow due to a combination of their chemical and electrochemical gradient + taking into consideration their conductance (can be modelled using Nerst equation)
-70mv resting potential as a result of more negative charges inside than outside of the cell
- leaky channels of K made the permeability of the membrane higher for K than Na
- Active Na+/K+ ATPase pump which removes 3Na and takes in 2K ions with the use of ATP (change in comformation)
Describe the action potential sequence and what ions are responsible
- depol = Na+ influx
- Repol = K+ leaving the cell
- Hyperpol = more negative thanresting potential
Describe the mechanism of action of Na+ ion channel
3 FUNCTIONAL STATES:
- Resting = activation closed, inactivation open hence overall CLOSED
- Depol: activation and inactivation gate open, hence overall OPEN (influx of Na+)
- Hyperpol: reading a voltage past the threshold triggers the closure of the inactivation gate -> hence overall closed
!! activation and inactivation gates have an equal and opposite sensitivity to the voltage, and this means there is only a fixed amount of time where ions can flow, and the time of the AP is constant
Factors that impulse propagation depends on (2)
- axon diamater: larger means faster impulse
- presence of myelin = faster impulse
What is the composition of myelin
LIPIDS (80%): cerebrosides and sphingomyelin (ceramide compounds), cholesterol, gangliosides (esp at presynaptic level bcos they are -ve and Ca2+ is attracted to them)
PROTEINS (20%): myelin specific proteins such as: PLP, MBP, MAG for stability and adhesion to axon –> mainly distributed in the juxtaparanode and internode region
what are the 2 types of myelination
- INTRINSIC: inherently encoded program with formation of myelin at the embryonic level + growth of myelin sheath over the course of NS development
- ADAPTIVE: DYNAMIC myelin remodelling in the number and size of myelin sheaths, activated by neuronal signals AFTER intrinsic myelination has occured
where is the cholesterol needed for myelin synthesis derived from?
NOT FROM NEURONS DIRECTLY–> they cant make it bcos they dont have the enzymes (only a tiny bit from acetylCoA accumulation that either leads to FA or cholesterol synthesis
MAIN SUPPLY: glial cells (via the APO system) - needs to be imported
General structure of synapse and function
-junction between two neurons containing a presynaptic/post synaptic membrane and the synaptic cleft
-presynaptic = NTs, mitochondria and organnelles
-postsynaptic = NT receptors
MAIN FUNCTION: impuse transmission + integration (stimulatory, inhibitory or both)
How does myelination affect signal propagation?
SALTATORY CONDUCTION: the only location where ion channels are present are at the nodes of ranvier (gaps in the myelin) - hence depol can only occur at those levels and there is a ‘jump’ in the induction of impulse from node to node
Electrical synapse description
- membranes are physically connected by aligned connexin subunits (forming gap junctions)
- allows direct ion flow at a very fast rate + can be bidirectional
!! very rare and only found in the eye and heart for specific purposes
Ways in which a synapse can be classified
- mechanism of action (electrical, chemical)
- location (axodendritic, axoaxonic, axosomatic, neuromuscular, neuroglandular)
Chemical synapse mechanism steps (X)
- AP reaches preSN
- this depol opens Ca2+ channels that allows Ca2+ entrance
- Ca2+ allows activation of NT vesicles that move towards the preS membrane + dock (using kiss and run method)
- release of NTs into synaptic cleft
- NTs bind to specific receptors on postSN and induce the opening of Na+ channels
- influx of Na+ causes a new AP in the postSN
- NTs in synaptic cleft are removed and recycled
Classes of NTs (2 diff ways to classify them)
- FUNCTION: inhibitory, excitatory or both (in which case it depends on the types of receptors present on postS membrane)
- DERIVATIVE: amino acid, peptides, monoamines, soluble gases, Ach
In what ways can a NT be removed from the synaptic cleft?
- enzymatic degradation
-proteolysis (for peptide NTs)
-reuptaken by preSN
-binding to preSN receptors (on the external leaflet only)
-enter into the circulation
-uptaken by supporting cells (glial cells)
What is the structure & composition of a NT vesicle
-NTs are originally synthesised outside vesicle and hence need to be inserted inside HOWEVER they are mainly charged and hydrophilic (so cant immediately cross membrane)
HENCE: membrane shows large expression of ATP-ase pumps (H+ gradient generator so NTs are imported via secondary transport)
-NT transporters
-VAMP2 (V-snare) for the docking to preS membrane
Describe the docking of the NT vesiscle on the preS membrane
- ACTIVATION OF SNARE COMPLEX: VAMP and synaprobrevin on vesicle binds with Syntaxin and SNAP25 on membrane
- Ca2+ influx which binds to the complex and neutralises it for fusion (otherwise 2 lipid membranes would experience repulsion)
- MUNC13/18 PROTEINS: bind onto complex to allow the vesicle to reach as close as possible to membrane
- KISS AND RUN DOCKING: only transient fusion of vesicle (not full collapse into membane), NT released into cleft, and vesicle is recycled
how is unidirectionality established in chemical synapses
- NTs synthesised in active form
- no receptors on preSN
- receptors on postSN
- clearance of NT from cleft so action doesnt persist
Ach (synthesis, action & degradation)
SYNTHESIS:: serine - 2 aminoethanol - choline - Ach (final step requires acetyl CoA derived from pyruvate from glucose)
ACTION: both S/I, cholinergic, muslce stimulation including GI system
DEGRADATION: hydrolysis by acetyl cholinesterase + taken up by presynaptic domain for recycling
dopamine (synthesis, action & degradation)
SYNTHESIS: tyrosine - LDOPA - dopamine
ACTION: inhibitory, reward mechanisms and motor activity, overexpressed in schizophrenia, underexpressed in parkinsons
DEGRADATION: uptaken by preSN, catabolised (via 2 diff pathways) into HOMOVANILLIC ACID which is then released in urine (and this is how we quantify amount of dopamine in the body)
Norepinephrine (synthesis, action & degradation)
SYNTHESIS: dopamine to norepinephrine (this needs VIT C, + this is the ONLY NT to be synthesised inside the vesicles instead of cytosol)
ACTION: both I/S, increases alertness of body + increases HR/BP
DEGRADATION: taken in by preSN or diffused to blood (cocaine blocks this recycling, leaving NT longer in the cleft and hence causing longer excitation)
Glutamate (synthesis, action & degradation)
SYNTHESIS: de novo synthesis from glucose via Krebs + glutamine cycle (1 glutamine makes 2 glutamate) –> bcos it cant cross BBB at low concs
ACTION: most common excitatory NT in brain, memory and learning functions
DEGRADATION: preSN receptors, intake into postSN, intake to glial cells (NOT DEGRADED IN CLEFT SO NO NH3 BUILDUP)
GABA (synthesis, action & degradation)
SYNTHESIS: glutamate to GABA (using PLP for decarboxylation)
ACTION: inhibitory, prevents overexcitation, underexpression can cause epilepsy
DEGRADATION: recycled to preSN or taken into astrocytes - transamination into glutamine to be recycled back to preSN cell
Serotonin (synthesis, action & degradation)
SYNTHESIS: tryptophan - 5hydroxytryptophan - serotonin
ACTION: inhibitory, sleeping/attention/ pain regulation and mood functions (underexpression can lead to depression)
DEGRADATION: catabolised used monoamine oxidases (MAOs) in the same way as dopamine, taken into glial cells or reuptake into preSN
what are the different receptor types of NTs
- Ach (nicotinic and muscarinic receptors)
- monoaminergic (a1/a2/b)
- aminoacid and peptidergic (GABA, glutamate, opiod receptors)
what controls the expression of receptors
EQUILIBRIUM - receptors synthesis (transcription): receptor recycling (clathrin mediated endocytosis)
–> this affects the density of the receptors on the membrane at pre/postSN and is involved in neuroplasticity
Botulism (Clinical point)
-paralytic illness caused by clostridium botulinum toxin
-food borne, infant, wound, iatrogenic or intestinal types
-spores consumed lay dormant until found in growth supporting conditions
SYMPTOMS: nausea, slurred speech, muscle weakness and paralysis (progressively worsening symptoms)
TREATMENT: antidote given, terminate exposure and monitor resp behaviour
