Inhibitory Synaptic Transmission and GPCR

ACh receptors

• nicotinic

• muscarinic

glutamate receptors

• NMDA

• mGluRs

• AMPA

examples of inhibitory NT

• GABA

• Glycine

what synapses do GABA and GLYCINE mediate

fast synaptic inhibition through activation of ionotropic receptors

regulation of inhibition is important as:

• Too much = loss of consciousness

• Too little = seizures

what are GABA receptors the site of action for

nuerosteroids, ethanol, benzodiazepines and barbiturates

mutations in glycine transporters

• hyperglycaemia

• Lethargy

• Seizures

what happens when glutamatergic receptors open

 membrane becomes more positive

what happens when GABA synapse activated

inhibitory response created as negatively charged ions enter so membrane potential becomes depolarising

how are  different sub-cellular regions of excitatory neurons controlled

distinct axonal projections

what happens if glutamate neurones become active

activates inhibitory neurone and releases inhibitory NT = feedback inhibition

glycine receptors

• ionotropic

• conduct Cl- ions

GABA A receptors

• ionotropic

• conduct Cl- ions

multimeric macromolecular complexes comprised of five subunits (they are pentameric).  Like the nAChR each subunit contains four transmembrane domains.

GABA B receptors

• Metabotropic

• coupled to G-proteins

what is strychnine

• competitive antagonist that binds to the α subunit

  • Causes convulsions and asphyxia

  • Hyperekplexia - Excessive startle responses due to a lack of glycinergic inhibition.

    

How does Benzodiazepine increase the action of GABA

by increasing the probability that the channel opens following the binding of GABA.  Only GABAA receptors that contain a γ subunit (in addition to α and β subunits) show potentiation by benzodiazepines

use of benzodiazepines

• anti-convulsant

• pre-operative sedatives

• hypnotics

N and C terminus of Muscarinic ACh receptor

• N terminus is extracellular and C terminus is intracellular

• Class A GCPR have binding sites formed by TM helices or extracellular loops

G - protein structure

• Heterotrimeric proteins --> composed of 3 non identical subunits

• G proteins are tethered to the intracellular face of the cell membrane close to GPCRs

• They are named so as activated by binding of GTP to alpha subunit

• GTP binding occurs as a result of an interaction between G protein and an activated GPCR

mechanism of G protein action

1. before ligand binding, the G protein is in an inactive state with GDP bound

2. agonist induced GPCR activation causes binding of GP trimer and displacement of GDP by GTP = GP activated

3. active G protein splits into alpha and beta subunits —> both able to activate or inhibit effector proteins

4. the alpha subunit has GTPase which removes a phosphate group by hydrolysis

5. G protein reverts to an inactive form and a and B subunits reform as a trimer

types of muscarinic receptors

• M1 - neural (slow)

• M2 - cardiac

• M3 - glandular  secretion, contraction of smooth muscle and vascular relaxation

GPCR in the heart

• Ach binds to M2 receptor and promotes opening of K channels

• K channel opening causes hyperpolarisation of cardiac muscle membrane potential --> Parasympathetic slowly of heart rate

  • Shortens duration of cardiac AP

  • Increases interval between cardiac AP

GPCR in smooth muscle

• Many GPCR stimulate the same signal transduction pathway --> 2 different transmitters act through distinct GPCR can have convergent actions on the same signalling pathway in the same cell

• In the CNS, 5-HT binding receptors promotes the opening of potassium channels through direct action of G protein By subunits