Farma 1.2. Neurotransmission/synaptic transmission

Diff types of synapses

1) Axodendritic: axon connects to dendrites
 ->most common (axon one neuron connects with dendrite of another)

2) Axosomatic: axon connects to cell body (soma)

3) Axoaxonic: axon connects to another axon

Opm: synapse= “to clasp”

Process when AP reaches presynaptic nerve terminal

1. Voltage-gated calcium channels open
 ->calcium ions enter nerve terminal

2. Release of NTs  
 ~already stored in vesicles due to activation of molecular processes inside nerve terminal by calcium

 ->often not enough vesicles available

 ->membrane of vesicles fuse with presynaptic membrane

 ->release of NTs in synaptic cleft via exocytosis

3. NTs bind to specific proteins/molecules (=receptors) in postsynaptic membrane

 ->can generate response of postsynaptic cell

 ->depending on type of receptor/NT: excitation/inhibition

 

4. Metabolic/catabolic processes to breakdown NTs or reuptake

Catabolic processes

=enzymatic destruction/breakdown (like MAO)

Metabolic processes

=reuptake

 1) Clathrin-mediated endocytosis (budding)

2) Ultrafast endocytosis & endosomal budding

3) Kiss-and-run

 =vesicles partially fuse & then quickly reclose for reuse of membrane

Clathrin-mediated endocytosis (budding)

=vesicle membrane is retrieved by presynaptic neuron through endocytosis

 ->it buds off from plasma membrane here

 =>reforms into new vesicles

Ultrafast endocytosis & endosomal budding

=fast, clathrin-independent pathway that retrieves membrane into endosomes (=internal organelle, sorting station for membrane components)

->regenerates vesicles from endosomes (endosomal budding)

Diff kinds of vesicles

1) Small vesicles: stores NTs

2) Large vesicles: can store neuropeptides AND/OR NTs

Few things control rate of NT release

1. Rate of cell firing

2. Probability of transmitter release

3. Auto- & heteroreceptors

Receptors

=essential for NTs to exert an action on the postsynaptic cell
->different kinds: autoreceptor, heteroreceptor, somatodendritic receptor

Autoreceptor

=receptor on presynaptic terminal (works as negative feedback mechanism)

 ->binds to its own NT: regulates/inhibits its own release

Heteroreceptor

=receptor that acts on other NTs systems to modulate their activity (found on various parts of neuron)

 ~response to NT: regulates release/synthesis of a different NT than the one it’s bound by

 =>can enhance or reduce release of NTs

Somatodendritic receptor

=modulates its own release of NTs: slows rate of cell firing (but doesn’t inhibit)

 ->located on cell body and dendrites (where neuron releases NTs that act on its own receptors in these areas)

Example autoreceptor

=apomorphine: agonist of dopamine

 ->inhibits specific type of interceptor: decreases breakdown of DA (causes vomiting)

4 main families of receptors

1. Ligand-gated ion channels
2. G protein-coupled receptors
 ->ionotropic & metabotropic receptors are main receptors for understanding neurotransmission 
3. Kinase-linked receptors
4. Nuclear receptors

Ligand-gated ion channels

=ionotropic receptors
1. NTs binds to receptor ->opens ion channel
2. Ions can enter cell which leads to hyper/depolarization

3. Cellular effects occur

->fast process: milliseconds

Bv.: Nicotinic ACH receptor, GABAa receptor

G protein-coupled receptors

=metabotropic receptors

1. NTs binds to receptor but doesn’t directly open ion channels (indirectly or via enzyme: uses second-messenger)

2. G-proteins involved: excitatory or inhibitory

3. Cellular effects occur
 ->longer process (seconds) but also lasts longer

Bv: Muscarinic ACH receptor, adrenoreceptors

Kinase-linked receptors

1. NTs binds to receptor -> protein is phosphorylated (phosphor is added to it)

2. Leads to gene transcription and protein synthesis

3. Cellular effects occur

 ->takes hours, but long-term changes of cell function

Bv. Cytokine receptors, insulin, growth factors

Nuclear receptors

=usually dependent on polar NTs

1. NTs binds to receptor by crossing cell membrane
2. Leads to cell transcription and protein synthesis

3. Cellular effects occur

 ->Takes hours, but long-term changes of cell function

Bv. Estrogen receptor, steroid receptor

First messengers

=extracellular signaling molecules that bind to cell-surface receptors

 ->NT’s and hormones

 ->activation of intracellular signaling pathways

 ->rely on second messengers (can’t cross cell membrane)

Second messengers

=non-protein intracellular signaling molecules

 ->calcium, cAMP, cGMP, IP3…

 ->pass on extracellular signals received at receptors

 ->can lead to phosphorylation by activating kinase

Chemical signaling

~requires presence of molecules on membrane of postsynaptic cell (receptors: sensitive to NT signal)

 ->several ways for NT receptors to alter activity of postsynaptic cell (almost all NTs discovered so far have more than one kind of receptor: receptor subtypes)

 ->perfect drug would only target 1 specific receptor type (& would cause much less side effects)

2 major families of receptors

Ionotropic receptors
1. Structure: 4/5 subunits that are assembled & then inserted into the cell membrane
2. Mechanism of action: contain an intrinsic ion channel that opens in response to NT or drug binding
3. Not coupled to 2^nd messengers
4. Fast speed of action
 ->pore instantly opens when NT binds & channel instantly closes when it leaves

 

Metabotropic receptors
1. One subunit (no pore)
2. Activate G proteins in response to NT or drug binding
3. Coupled to 2^nd messengers
4. Slower

Biochemical cascade (activation metabotropic receptor)

1. Activate G protein (~”signal starters” of cascade)

2. Stimulate/inhibit effector enzyme in membrane of postsynaptic cell

3. Increase synthesis or breakdown of 2nd messenger

4. Biochemical or physiological changes in postsynaptic cell due to altered levels of 2nd messenger

G-protein can do 2 things

1. Alter opening of a G-protein-gated ion channel

2. Stimulate/inhibit effector enzyme (that either synthesizes or breaks down a 2nd messenger)

 

G-proteins & 2^nd messengers control cellular effector systems (leads to biochemical & chemical response)

Mechanism of 2^nd messenger

=work by activating protein kinases and thus altering functioning of protein

 ->can produce and profound changes in postsynaptic cells

(even inducing long lasting changes to gene expression)

 ->because of long-lasting effect, 2nd messenger plays big role in memory, long term potentiation & addiction

Protein kinases

=proteins that phosphorylate another molecule

Inactivation of a NT

NT molecules can be inactivated by:
1. Enzymatic breakdown
2. Reuptake by the axon terminal
3. Uptake by nearby glial cells
 =>cellular uptake is mediated (controlled/regulated) by specific membrane transporters for each NT!

Neurotransmitters

=chemical messengers that transmit a signal from a neuron across the synapse to a target cell

 ->100+ substances to date identified as NTs

 ->some used across vast/large areas of NS, others more locally in specific systems

Action of NTs

1) Synthesis & storage

 ->some are transported from cell nucleus, others synthesized in axon terminal

2) Release: in response to action potential, by exocytosis

3) Receptor action: NTs crosses synaptic cleft, binds to receptor + activates it

4) Inactivation: NT is taken back to terminal/inactivated in cleft

~all steps are targeted by neuropharmacological agent

Types of NTs

1) Small-molecule neurotransmitters

 ->amino acids: bv. Glutamate, GABA

 

2) Peptide neurotransmitters

 ->larger molecules made of multiple amino acids

 Bv. Endorphins, oxytocin, vasopressin, substance P

 

3) Lipid neurotransmitters

 ->fatty signaling molecules: bv. endocannabinoid

 

4) Gaseous neurotransmitters

 ->gas: bv. Nitric oxide, carbon monoxide

Examples of pharmacological drugs used

1. L-dihydroxyphenylalanine (L-DOPA) =precursor to DA

  ->used Pt Parkinson, stimulates NT release

2. 5-hydroxytryprophan (5-HTP) =precursor to serotonin (5-HT)

 ->used in depression

Synaptic plasticity

1) Various kinds of experiences can strengthen/weaken synaptic connections (eg learning)

 

2) Even in adulthood axons can grow new terminals
 ->dendrites can expand or contract their branches and/or gain /lose spines than synapses can be created/lost

 

3) Not only due to sensory/environmental st. or learning & memory

 

4) Psychoactive drugs can profoundly trigger synaptic plasticity (especially under repeated exposure)

Possible functions of drug

1. Serves as NT precursor

2. Inhibits NT synthesis (inhibits enzyme)

3. Prevents storage of NT in vesicles

4. Stimulates/inhibits release of NT

5. Stimulates/blocks postsynaptic receptors

6. Stimulates autoreceptors -> thus inhibiting release of NT

7. Blocks autoreceptors -> thus increasing release of NT

8. Inhibiting NT degradation

9. Inhibiting reuptake