metabotropic receptors and synaptic neuromodulation

k shaker channels

activate quickly and then deactivate

delayed rectifier k channels

activate slowly and then plateau (they do not inactivate)

modulation via g protein coupled receptors

- located at terminal or post synaptic side
- 7 transmem alpha helices structure in plasma domain (ligand binds EC side and interact with g proteins on IC side)
- type of g protein they interact with determines type of response the receptors have
- activated by NT
- no ion channels
- slow responses
- indirect effects on channels and receptors
- neuromodulation

types of metabotropic receptors

- modulate PA and S functions
- glutamate
- ach post ganglionic PA
- noadrenaline post ganglionic S
- serotonin
- dopamine

what signals do Gi/Gs coupled receptors modulate

cAMP signals

Gi coupled receptors

- decrease function of cAMP pathway
- Gi inhibits adenylyl cyclase so reduces levels of cAMP and active PKA

Gs coupled receptors

- increase function of cAMP pathway
- when activated it stimulates activity of adenyly cyclase enzyme
- leads to production of cAMP via ATP
- cAMP activates PKA
- when PKA is bound to cAMP the catalytic break away and phosphorylate targets eg channels (channel closes)

PLC and Gq coupled receptors

- Gq activation activates phospholipase beta enzyme
- this activates PIP2 (lipid molecule)
- PIP2 is hydrolysed releasing IP3
- IP3 release can result in release of ca from stores
- ca acts as signalling molecule leading to channel activation
- Gq can produce diacylglycerol
- this activates PKC which effects phosphorylated channels and receptors that effect synaptic function

what are the two modes of action

- direct and indirect
- involve diffusible messengers stimulated downstream of G protein function
- both actions can occur at different locations

indirect effects

- action via second messenger/enzyme pathways
- lead to change in target protein function of channels and receptors

direct effects

- action of g proteins
- g beta gamma subunits interact with taregt channels (k (GIRK) and ca)

3 sites of action

- locations allow regulation of different aspects of synaptic function
- pre synaptic
- post synaptic
- cell body

pre synaptic action

influence how much NT is released

post synaptic action

- influence number of receptors available to recieve signal
- influence how permeable receptors are to ions
- influence excitability

Indirect postsynaptic modulation

- cholinergic signalling in autonomic ganglia
- act on muscarinic receptors (slows EPSP)
- nicotinic receptors
- both receptors activated at same time but muscarinic effect is much slower

when we stimulate pre synaptic neurones...

- ach released
- rapid fast EPSP mediated by nicotinic receptors
- ion channels open and na influx
- quick depolarisation

nicotinic receptor

- ionotropic receptor that produces a fast response to Ach
- bind ach causing fast EPSP

what are muscarinic receptors coupled by

- Gq
- activates phospholipase C
- hydrolyses PIP2 releasing IP3

PIP2 action before hydrolysis

- interacts with m type k channels in mem
- channel left open and remains open when PIP2 nearby
- when muscarinic receptor activated PIP2 lost via hydrolysis
- results in m type channel closing inducing slow EPSP
- = slow k efflux
- closure of channel = longer repolarisation

Role of slow EPSP in autonomic neurones

- cell converted from one that fires a single response to one that produces multiple AP

Direct modulation of post synaptic function

- eg cardiac muscle
- activation of muscarinic ach slow HR (decrease excitability of the heart)
- GIRK k channel opens = hyperpolarisation
- G protein beta-gamma subunit bind directly to GIRK causing it to open

GIRK

G protein coupled inwardly rectifying K+ channel

modulation of GIRK by g protein subunits

- k channel activity increases do to ach
- ach activates GIRK
- ach release stimulates muscarinic receptor = triggers direct effect
- muscarinic AchR transduces signal to GIRK

Direct presynaptic modulation - synaptic inhibition

- GPCR activation due to release from same or another presynaptic neurone
- modulation of ca channels regulates synaptic release of NT
- ach can be released for pre synaptic cell
- NA can block action of ca

Presynaptic inhibition of V gated Ca2+ channels

- NA activates adrenoceptor which inhibits ca channels via beta-gamma signalling
- ca channels close
- NF = reduced ca entry leads to reduced NA release so dec synaptic transmission

Indirect presynaptic facilitation

- function = facilitation of N T release often in sensory pathways
- diffusible cAMP signals lead to PKA activation and closure of delayed rectifier k channels
- = slower repolarisation
- prolonger AP
- leads in inc ca influx
- results in inc vesicle mobilisation and release

what is pre synaptic facillitation

- where synaptic receptors get enhanced
- respond to stimuli in environment

release of serotonin effect

- activates metabotropic serotonin receptors
- through Gs cAMP activates and closes delayed k rectifiers

- bigger EPSP
- broader AP
- more ca channels activated = inc influx
- more NT released

what happens if you reduce number of delayed rectifier channels

- AP gets broader
- repolarisation is slower and less effective
- AP lasts longer
- they activate ca channels for longer so there is inc ca influx
- so more NT released causing a bigger EPSP recorded from post synaptic cell

5HT receptor modulation of sensory motor circuit in a mollusk

- gill withdrawal
- draws water in through siphon into gill for respiration
- NT = glutamate
- regulated by serotonin - - 5HT activates pre synaptic facilitation via Gq GPCR = gill withdrawal enhanced