In the 1970s, the humblest amino acid, _______, was established as an inhibitory transmitter in the spinal cord

Glutamate in the CNS comes mainly from either _____, via the Krebs cycle, or _____, which is synthesized by ____cells and taken up by the neurons.

glutamate is stored in synaptic vesicles and released by____-dependent exocytosis;

Glutamate taken up by astrocytes is converted to glutamine and recycled, via transporters, back to the neurons, which convert the glutamine back to glutamate.

In what pathological situation would the statement above occur?

AMPA receptors, and in certain brain regions kainate receptors, serve to mediate _____ synaptic transmission in the CNS – absolutely essential for our brains to function.

NMDA receptors (which often coexist with AMPA receptors) contribute a slow component to the ______ synaptic potential.

NMDA, kainate and AMPA receptors are also expressed on _____where they can enhance or reduce transmitter release.

SUBUNIT COMPOSITION

tetramers consisting of GluN1-3 subunits

SUBUNIT COMPOSITION

Tetramers consisting of GluA1-4 subunits

SUBUNIT COMPOSITION

tetramers consisting of GluK1-5

ENDOGENOUS AGONISTS

Receptor site: _______ -> Modulatory Site is Glycine and D-serine.

ENDOGENOUS AGONISTS

for AMPA and Kainate

NMDA ANTAGONISTS

Receptor site: AP5 + CPP -> Modulatory site: ________

AMPA ANTAGONISTS

CHANNEL BLOCKERS

The following are CB for what ionotropic glutamate receptors?

Dizocilpine (MK801)

Phencyclidine

Memantine

Mg

EFFECTOR MECHANISM

Ligand-gated cation channel (slow kinetics, high Ca2+ permeability)

EFFECTOR MECHANISM

Ligand-gated cation channel

(fast kinetics; channels possessing GluA2 subunits show low Ca2+ permeability)

EFFECTOR MECHANISM

Ligand-gated cation channel (fast kinetics, low Ca2+ permeability)

LOCATION FOR GLUTAMATE RECEPTOR

Postsynaptic (some presynaptic, also glial) Wide distribution

LOCATION FOR GLUTAMATE RECEPTOR

postsynaptic and glial

LOCATION FOR GLUTAMATE RECEPTOR

PRE- + POST-Synaptic

FXN OF GLUTAMATE RECEPTOR

NMDA?

FXN OF GLUTAMATE RECEPTOR

Fast epsp

Presynaptic inhibition

Limited distribution

AGONISTS ACTING ON GLUTAMATE, GABA, AND GLYCINE RECEPTORS

L-Glutamate

AGONISTS ACTING ON GLUTAMATE, GABA, AND GLYCINE RECEPTORS

GABA

AGONISTS ACTING ON GLUTAMATE, GABA, AND GLYCINE RECEPTORS

glycine

AGONISTS ACTING ON GLUTAMATE, GABA, AND GLYCINE RECEPTORS

L-Aspartate

AGONISTS ACTING ON GLUTAMATE, GABA, AND GLYCINE RECEPTORS

Muscimol

Baclofen

AGONISTS ACTING ON GLUTAMATE, GABA, AND GLYCINE RECEPTORS

L-AP-4

KAINATE

AMPA

NMDA

EFFECTS OF EXCITATORY AA RECEPTOR ANTAGONIST ON SYNAPTIC TRANSMISION

AP5 (N-methyl-Daspartic acid [NMDA] antagonist) prevents

long-term potentiation (LTP) in the rat hippocampus without affecting the _____

AMPA RECEPTORS RE PRESENT IN BOTH ASTROCYTES AND NEURONS

ionotropic glutamate receptors are most abundant in the ___, ______ and sensory pathways

Main sites of drug action on N-methyl-Daspartic acid (NMDA) and GABAA receptors

Both are multimeric.

Both Can block ion channel at one or more distinct sites.

SPECIAL FEATURES OF NMDA RECEPTORS

Q1) permeability to Ca?

Q2) improves entry of what ion?

Q3) when the cell is normally polarized, receptors are blocked by what ion?

Q4) What is required to activate NMDA receptors?

Q5) Functions as an endogenous activator or the glycine site on the NMDA receptor?

Q6) Endogenous polyamine that acts at an allosteric site distinct from that of glycine to facilitate channel opening?

Q7) _______ & _____ activate NMDA receptors and may be endogenous activators in the brain.

Q8) Selective blocking agents for NMDA-operated channels.

metabotropic glutamate receptors (mGlu1–8) which are unusual in showing no sequence homology with other ______–coupled receptors

METABOTROPIC GLUTAMATE RECEPTORS

Group __ and __ mGlu receptors are mostly presynaptic receptors and their activation tends to reduce synaptic transmission and neuronal excitability

METABOTROPIC GLUTAMATE RECEPTORS

(Members)

mGlu 2 + 3

METABOTROPIC GLUTAMATE RECEPTORS

(members)

mGlu 4-8

METABOTROPIC GLUTAMATE RECEPTORS

(members)

mGlu 1 + 5

METABOTROPIC GLUTAMATE RECEPTORS

(G protein coupling)

Gq?

Gi/G0?

METABOTROPIC GLUTAMATE RECEPTORS

(Agonist)

Eglumegad

L-AP4

(S)-3,4-DCPG

METABOTROPIC GLUTAMATE RECEPTORS

(Antagonist)

LY367385

S-4-CPG

METABOTROPIC GLUTAMATE RECEPTORS

(neuronal location based on group)

somatodendritic

somatodendritic and nerve terminals

nerve terminals

_____ - is found only in the retina

METABOTROPIC GLUTAMATE RECEPTORS

mGlu 8 + 1 + 5 are selective

Synaptic plasticity underlies much of what we call ‘brain function’, allowing it to be influenced by ______

____ - is a prolonged (hours in vitro, days or weeks in vivo) enhancement of synaptic transmission that occurs at various CNS synapses following a short (conditioning) burst of high-frequency presynaptic stimulation.

Long-term depression (LTD) - is produced at some synapses by a longer train of stimuli at ______ frequency.

INOTROPIC GLUTAMATE RECEPTOR ANTAGONISTS

Kynurenic acid + 7-chloro-kynurenic acid act by blocking the ______.

Which of the two is more potent?

Which substance specializes in blocking the channel?

What are the only 2 NMDA receptor antagonists which have shown to be beneficial in cases with depression and Alzheimer’s?

Selective NMDA receptors that aid in the treatment of neuro degeneration and CNS side effects?

Perampanel (non-competitive AMPA receptor), this receptor kainate antagonists (Gluck-1) appear promising for treatment of ________

Selective Negative Allosteric modulators may have fewer SFX than previous generations of orthosteric antagonists.

MMETABOTROPIC GLUTAMATE RECEPTOR ANTAGONISTS

Antagonists or negative allosteric modulators acting of group 1 mGlu receptors have potential for the treatment of ________

IONOTROPIC GLUTAMATE RECEPTOR

Ampalex and Piracetam are positive allosteric modulators have shown to improve _____

______ - has shown to up-regulate the production of nerve growth factors such as Brain Neurotrophic Factor (BDNF)

_____ - on clinical trial for drug-induced respiratory depression

METABOTROPIC GLUTAMATE RECEPTORS

Group 2 and 3 receptors are located presynaptically on nerve terminals and agonists at these receptors decrease ______ release

Y-AMINOBUTYRIC ACID

What is the main inhibitory transmitter in the brain?

What is the main inhibitory receptor in the spinal cord and brainstem?

Y-AMINOBUTYRIC ACID

GABA is abundant in the _____ system

How abundant is GABA?

At the GABAnergic nerve terminals what recycles GABA ?

GABA transport is inhibited by ?

Which one is used to in the treatment of epilepsy?

From the striatum -> Substantia nigra + globus pallidus there are _____ GABAnergic tracts.

EXCITATORY AA

Main fast excitatory transmitters in the CNS?

EXCITATORY AA

Glutamate formed mainly from the Karen’s cycle intermediate _____ by the action of GABA transaminase.

How many:

Ionotropic glutamate receptors?

Metabotropic receptors?

3 Ionotropic receptors regulating cation channels?

AMPA and KAINATE receptors are involved in ?

MNDA is mainly involved in?

Competitive NMDA receptor antagonists include?

The NMDA-operated ion channel Is blocked by ?

NBQX is an AMPA and _____ receptor antagonist.

NMDA receptor activation is increased by endogenous poly amines, such as______

Excitotoxicity is due to ?

______ - Are dimeric G protein-coupled receptors

Inocitol Triphosphate formation and Intracellular Ca+ release is achieved by the coupling of ?

GABA RECEPTORS: STRUCTURE AND PHARMACOLOGY

GABA-A acts on ?

GABA-B acts on

Extrasynaptic GABA-A contain ___ and ___ subunits as well as the delta subunit.

They have higher affinity for GABA, and are highly sensitive to ______ and _____

GABA-B receptors are located pre- and postsynaptically. They are class ____ G protein-coupled receptors that couple through ____, to inhibit voltage-gated Ca+ channels

-> to open K channels -> to inhibit _______

Activation of the GABA-B receptor occurs when GABA binds to the extracellular domain of the ___ subunit.

(Known as the Venus Fly trap )

INHIBITORY AMINO ACID RECEPTORS

GABA-A effector mechanism?

Fxn is at postsynaptic inhibition

(Fast ipsp and tonic inhibition)

Fxn is presynaptic inhibition (decreases Ca entry)

+

Postsynaptic inhibition (increased K permeability)

Fxn of Glycine?

INHIBITORY AA: GABA + GLYCINE

Main inhibitory transmitter in the brain

INHIBITORY AA: GABA AND GLYCINE

GABA is formed from glutamate bu type action of ???

_____ - occur mainly postsynaptically, and are directly coupled to chloride channels, the opening which reduced membrane excitability.

_____ - is a specific GABA A agonist, and the convulsant Bicuculline is an antagonist.

_____ - Receptors are heterodimers G protein-coupled receptors.They cause pre- and postsynaptic inhibition by inhibiting Ca+ channel opening and increasing K+ conductance.

For instance?

Inhibitory transmitter mainly in the spinal cord, acting on its own receptor.

(Structurally and functionally similar to GABA A receptor)