Chemical Mediators 4 Flashcards
What are amino acids transmitters:
Drugs that affect the CNS by affecting the central synaptic transmission.
Amino acid transmitters can cause excitatory effects at synapses, or can produce inhibitory effects on the post-synaptic membrane.
Fast transmission of information
Inhibitory transmitters
Excitatory transmitters
Types of excitatory and inhibitory transmitters:
Glutamate is excitatory transmitter in CNS
Synthesised in terminal
Removed from synapse by active uptake into presynaptic terminal
GABA (gamma amino butyric) is usually inhibitory in the brain
Produced in nerve terminal from a.a. in diet, released into synapse.
Removed from synapse by active reuptake into presynaptic terminal
Glycine is usually inhibitory in the spinal cord (but may have multiple actions in the brain)
GABA: COO- CH2 CH2 CHNH3+
Glutamate: COO- CH2 CH2 CHNH3+ COO-
Glycine: COO-CH2 NH2
Effects of excitatory and inhibitory
transmission on the post-synaptic cell:
Excitatory transmitters depolarise the membrane producing EPSP’s (excitatory post-synaptic potentials).
Inhibitory transmitters hyperpolarise the membrane producing IPSP’s (inhibitory post-synaptic potentials).
Metabolism and release of amino acids:
Glutamate, an excitatory amino acid, is widely and uniformly distributed in the CNS with a concentration significantly higher than in other tissues. In the CNS, it primarily originates from glucose via the Krebs cycle or glutamine synthesized by glial cells and taken up by neurons, with minimal contribution from the periphery. The interconnected pathways for the synthesis of excitatory (EAAs) and inhibitory amino acids (such as GABA and glycine) present a challenge for studying individual amino acids’ functional roles. Experimental manipulations of transmitter synthesis are hindered by the fact that disturbance in any one step affects both excitatory and inhibitory neurotransmitters.
Metabolism of transmitter amino acids in brain:
Slide 8-12
Glutamate receptors:
Four main subtypes of EAA receptors can be distinguished:
NMDA receptors
AMPA receptors
Kainate receptors
Metabotropic receptors
The first three are ionotropic receptors. The channel consists of four subunits, each with the ‘pore loop’ structure
The metabotropic receptors are G-protein-coupled receptors linked to intracellular second messenger systems and comprise eight subtypes in three main classes.
Binding studies show that glutamate receptors are most abundant in cortex, basal ganglia and sensory pathways
NMDA receptors:
The NMDA receptors and their associated channels have been studied in more detail than the other types and show special pharmacological properties, which are postulated to play a role in pathophysiological mechanisms.
Main sites of drug action on NMDA receptors. Receptors are multimeric ligand-gated ion channels. Drugs can act as agonists or antagonists at the neurotransmitter receptor site or at modulatory sites associated with the receptor. They can also act to block the ion channel at one or more distinct sites.
Highly permeable to ca2+ as well as to cations so activation f NMDA receptors is particulates effective in promoting Ca2+ entry. Blocked by mg2+ shows voltage dependence
Activation of NMDA:
Requires glycine as well as glutamate
Binding site for glycine is distinct from glutamate binding site and both have to be occupied for the channel to open
The concentration of glycine required depends on subunit composition of NMDA receptor; for some NMDA receptor subtypes, physiological variation of the glycine concentration may serve as a regulatory mechanism, whereas others are fully activated at all physiological glycine concentrations
Competitive antagonists at the glycine site indirectly inhibit the action of glutamate.
Recently, d-serine, has been found to activate the NMDA receptor via the glycine site and to be released from astrocytes.
Facilitation of NMDA by glycine.
Slide 20-22
Functional role of glutamate receptors;
NMDA receptors (which often coexist with AMPA receptors) contribute a slow component to the excitatory synaptic potential.
Metabotropic glutamate receptors are linked either to inositol trisphosphate production and release of intracellular Ca2+, or to inhibition of adenylyl cyclase .
They are located both pre- and postsynaptically, like other glutamate receptors, and also occur on astrocytes.
Their effects on transmission are modulatory rather than direct, comprising mainly postsynaptic excitatory effects (by inhibition of potassium channels) and presynaptic inhibition (by inhibition of calcium channels).
In general, it appears that NMDA and metabotropic receptors play a particular role in long-term adaptive and pathological changes in the brain, and are of particular interest as potential drug targets.
AMPA/kainate receptors, on the other hand, are mainly responsible for fast excitatory transmission, and if they are fully blocked, brain function shuts down entirely; nevertheless, they too are involved in synaptic plasticity.
What is GABA?
GABA is the most common inhibitory transmitter in the CNS and has many functions, including motor co-ordination., glycine is also important.
GABA inhibits synaptic transmission in the brain and retina.
Abnormalities of GABA transmission are implicated in a number of clinical conditions such as epilepsy, anxiety, Huntington’s disease and insomnia. GABA occurs in brain tissue but not in other mammalian tissues, except in trace amounts. It is particularly abundant (about 10μmol/g tissue) in the nigrostriatal system, but occurs at lower concentrations (2-5μmol/g) throughout the grey matter.
There are two receptors for GABA, A and B. The GABA A receptor forms a chloride channel when the ligand binds. The GABA B receptor is a metabotropic receptor.
Synthesis of GABA:
GABA is formed in axon terminals from glutamate by the action of glutamic acid decarboxylase (GAD), an enzyme found only in GABA-synthesising neurones in the brain.
Metabolism and storage of GABA:
GABA is destroyed by a transamination reaction in which the amino group is transferred to α-oxoglutaric acid (to yield glutamate), with the production of succinic semialdehyde and then succinic acid.
This reaction is catalysed by GABA transaminase (GABA-T), which is inhibited by vigabatrine, a compound used to treat epilepsy.
GABAergic neurones and astrocytes take up GABA via specific transporters, and it is this, rather than GABA transaminase, which removes the GABA after it has been released.
GABA transport is inhibited by guvacine and nipecotic acid.
GABA Receptors: Structure and pharmacology
GABA acts on two distinct types of receptors:
GABAA receptor, being a ligand-gated channel
GABAB receptor, being a G-protein-coupled receptor.
GABAA receptors belong to the same structural class as nicotinic acetylcholine receptors.
They are pentamers, most of them composed of three different subunits (α, β, γ), each of which can exist in three to six molecular subtypes.
GABA (A) receptor location:
GABAA receptors located postsynaptically mediate fast postsynaptic inhibition, the channel being selectively permeable to Cl-.
GABAA receptors located presynaptically are responsible for slow inhibitory effects produced by GABA diffusing further from its site of release.
Because the equilibrium membrane potential for Cl- is usually negative to the resting potential, increasing Cl- permeability hyperpolarises the cell, thereby reducing its excitability.
