chap 2: cellular signal transduction mech

Ionotropic receptors

• type of ion channel

• semi selective

• integral mem protein

• activate by ligand signal

2 types of acetylcholine receptors

1. nicotonic (nAChRs)

2. Muscarinic (mAChRs)

nicotinic (nARhRs)

• fast ion channel

• 6 subunits & give depolarization/ excitatory signals

• ligands: Ach

  • binds with high affinity → shape change

  • opens conduction pathway → Na+ & Ca2+ rush in

• ex: nicotine can bind and mimics neurotransmitter

muscarinic (mAChRs)

• use G proteins to create slower rxn (G-protein coupled receptors)

• ligand: Ach

  • activates G protein and 2nd chemical messenger to produce downstream effect & more chemical signals in cell

• ex: muscarine can mimic neurotransmitter

what are two general Glutamate receptor themes

• ionotropic

  • AMPA & NMDA (learning, memory, neuron excitotoxicty, depression)

  • ion channel

• metabotropic:

  • mGluR GPCRs

  • indirect, 2nd chemical messenger

Glutamate receptors

• membrane proteins

• require at least two ligands for activation

  • majority glutamate; glycine

• 4 distinct subunits

• ex: AMPAR, conducts Na+

what are the 4 receptor domains of glutamate receptor

• NTD: N-terminal

• LBD: ligand-binding

• TMD: transmembrane

• CTD: C-terminal

what happens when ligand binds to glu receptor?

• LBD changes shape → TMD changes shape -→ activation

NMDA (glutamate) receptor

• multiple activation steps

• req both glutamate & glycine

• Ca2+ conduct

• resting: Mg+ blocks the channel

• depolzarization kicks Mg2+ blocking

• too much Ca2+ rushing may kill neuron if not regulated

GABA receptors

• gamma (y) aminobutyric acid receptor

• ligand: GABA (NT)

2 gaba receptor themes

• ionotropic: GABA (a) receptors

  • key drug targets for anxiety, epilepsy

• metabotropic: GABA (b) receptors

GABA (a) receptor

• structure is closely related to nAChR

• 5 receptor subunits

  • depends on dif combinations → dif unique functions

• Cl- conduct, inhibtory, dec neuronal excitability, hyperpolarization

• 
  

cholinergic receptor

• a receptor that responds to acethylcholine

where can AChR be found?

• in cholinergic synapses

  • nicotinic synapse

  • muscarinic synapse

• both synapses function and structure are similar

example of ionotropic receptor at synapse

1. ap arrives in presynaptic terminal

2. AP triggers NS rel from vesicle to cleft

3. NS bind and activate postsynaptic receptor

   1. positive charges flow in (Na+, Ca2+)

4. (+) influx → mem more positive

   1. activate voltage-gated ion channels & AP stimulate or some response

G protein coupled receptors & elements of functional unit

• receptor

• G protein

  • 3 subunit types

• effector

Big (heterotrimeric) g proteins

• there’s also small G protein

• made of 3 protein subunits (a, b, y)

  • a binds GTP: on

  • GTP hydrolyzes: off

GEF: Guanine nucleotide Exchange Factor

• helper

• switches Ga from off to on

what is the GEF for Ga?

activated cell surface receptors

• activated GPCR acts as GEF

• GDP rel, GTP binds to Ga, turns it on

does Ga have its own GTPase activity?

• yes, it can hydrolyze its own GTP

G protein nucleotide binding cycle

1. no activation: Gα is bound to GDP w/ βγ.

2. A receptor activates a GEF, which promotes GDP release.

3. GTP replaces GDP on Gα → Gα becomes active (On).

4. downstream effectors.

5. A GAP (separate g protein) act as an accelerator to GTP hydrolysis → GTP → GDP + Pi.

6. Gα-GDP reassociates with βγ, returning the G protein to its inactive state.