BIO 448 - Neurotransmitter I

ionotropic receptor

aka ligand gated ion channels

directly coupled receptor

produces FAST postsynaptic responses

metabotropic receptors

G-protein coupled receptors

produces SLOW postsynaptic responses

use second messengers to indirectly act on ion channels

Types of small molecule NTs

• acetylcholine

• amino acids (glutamate, aspartate, GABA, glycine)

• Purines (ATP)

• Biogenic acids

  • catecholamines (dopamine, norepinephrine, epinephrine)

  • indoleamine (serotonin)

  • imidazole amine (histamine)

enzyme, cytoplasm.

small molecule NTs are encoded from the nucleus, the RNA is translated by an ___ in the ___, then are slowly transported along the axon. They diffuse everywhere in the nerve cell.

enzyme will package them locally from precursor in the presynaptic terminal as it is more efficient than to wait for the slow transport from the cell body.

acetylcholine

• transmitter at neuromuscular junction and in CNS

• important roles in autonomic nervous system

• synthesized from choline and acetate

• degraded extracellularly by acetylcholinesterase (AChE)

choline, acetate, choline acetyltransferase

acetylcholine is synthesized from ___ which is an essential dietary component, and ___ which is donated by acetyl coenzyme A which is an enzyme used in glycolysis.

It is made by the enzyme ___ (CAT).

Ach metabolism

1. choline acetyltransferase put together choline and acetate to make acetylcholine

2. ACh is packed by vesicular acetylcholine transporter

3. ACh is released in synaptic cleft, binds to receptor

4. degraded by acetylcholinesterase in synaptic cleft

5. choline is recycled by Na+/choline transporter

Sarin nerve gas

• man-made agent originally created as a pesticide in 1938 but developed further during WWII

• interfere with signals between nervous system and muscle fibers

• blocks acetylcholinesterase

• prolonged binding caused repeated firing, causing overstimulation of muscles

• shutdown of respiratory system and other bodily systems

short-term memory

acetylcholine also involved with brain synapses that deal with ___

especially found in hippocampus

nicotinic receptors

• nAChR

• ionotropic/ligand-gated receptors

• agonists = ACh and nicotine

• antagonists = curare

• neuromuscular junction of skeletal muscles and in the brain

• diffusion Na+ and K+ across receptor causes depolarization (EPP)

5

in the neuromuscular junction nicotinic receptors are heteromeric multimers that have __ subunits of different proteins: 1 gamma (epsilon in embryonic brain), 1 beta, 2 alpha, 1 delta

2, 3

in the brain nicotinic receptors are heteromeric multimers that have 5 subunits of different proteins: __ alpha, __ beta

alpha

ACh ONLY bonds to the __ subunit, aka 2 binding sites per receptor

ACh receptors kinetics

1. ACh molecules bind to alpha subunits of nicotinic receptor

2. receptor undergoes a conformational change

3. channel opens

4. cations pass through due to large pore size (Na+ and K+)

5. since resting membrane potential is close to equilibrium potential of potassium, mainly Na+ ions flow through

muscarinic receptors

• metabotropic receptors aka G-protein coupled receptors

• agonists: ACh and muscarine

• antagonist: atropine

• made of a SINGLE protein

• act indirectly on ion channels via second messengers

• found at neuromuscular junctions of cardiac and smooth muscles and glands but also in brain and autonomic nervous system

• agonist muscarine found in mushrooms

7

like most G-protein coupled receptors, muscarinic receptors are made of __ transmembrane domains and a SINGLE binding site for ACh

5

there are __ subtypes of muscarinic receptors, all made of a single protein, each bound to different types of G-proteins with different postsynaptic effects

glutamate

most important excitatory NT in the brain

elevated extracellular concentration of __ causes neural injury and therefore is toxic to the brain

it’s a non-essential amino acid

does NOT cross BBB, meaning that it is synthesized in neurons from glutamine

glutamate-glutamine cycle

1. glutamine turned into glutamate by glutaminase

2. glutamate packed into vesicles by vesicular glutamate transporters

3. released into synaptic cleft

4. Taken back into neuron by EAAT (excitatory amino acid transporters) OR taken up into glial cell (most likely an astrocyte) by EAAT and turned into glutamine by glutamine synthetase

5. glutamine released from glial cell and taken up into neuron by specialized transporters to be reused

mitochondrial

glutaminase, aka enzyme making glutamate from glutamine, is a __ enzyme

maintain supply, action

reasons glial cell and neuron cooperate:

• ___ of glutamate

• terminate postsynaptic glutamate ___

ionotropic glutamate receptors

• NMDA

• AMPA

• Kainate

AMPA

• ionotropic glutamate receptor

• agonist: alpha-3-hydroxy-5-methyl-4-isoxazole propionate

• classic FAST EPSP via increased conductance to monovalent cations (K+, Na+)

• fast and short acting responses

• big negative inward current depolarizing cells, shut down gradually

Kainate

• ionotropic glutamate receptor

• agonist: kainic acid

• classic FAST EPSP via increased conductance of monovalent cations (Na+, K+)

• fast and short acting responses

• small negative inward current depolarizing cells, shut down gradually

NMDA

• ionotropic glutamate receptor

• agonist: N-methyl-D-aspartate

• EPSP requires BOTH the presence/binding of glutamate AND cell depolarization (because magnesium gets stuck in channel until depolarization kicks it out)

• permeable to K+, Na+, Ca2+

associative property

because both the binding of glutamate and the depolarization of the neuron are necessary for NMDA to generate current and properly open, it is said that NMDA receptors have ____

metabotropic glutamate receptors

• group I (mGlu1 and 5)

• group II (mGlu2-3)

• Group II (mGlu4 and 6-8)

• ALL generate a slow but persistent responses via second messengers

• play a role in synaptic plasticity, learning, memory, anxiety and pain

• found in postsynaptic neurons in hippocampus, cerebellum, cerebral cortex

synaptic plasticity

ability of connection, or synapse, between two neurons to change in strength.

Metabotropic glutamate receptors play a role in ___

cell type

all effects of metabotropic glutamate receptors are ___ specific due to what type of proteins are expressed in this specific cell type.

GABA

• major inhibitory NT in brain

• synapses for this neurotransmitter are formed before the glutamatergic ones

• 1/3 synapses uses __ as inhibitory NT

• most commonly found in interneurons circuits

glutamic acid decarboxylase (GAD)

enzyme synthesizing GABA from glutamate

gene/protein NOT expressed in glutaminergic neurons because you wouldn’t want glutamate to be converted into anything else

aka gene/protein that the excitatory neurons do NOT have

glucose

GABA is made from glutamate which is a non-essential amino acid metabolized from __

pyridoxal phosphate

The Glutamic acid decarboxylase which is the enzyme making GABA requires a cofactor named ___ which is another name for the vitamin B6

deficiency in this cofactor leads to seizures as GABA cannot be synthesized

vesicular inhibitory amino acid transporters

GABA packed into vesicles by ___ aka VIAAT

GABA transporter

GABA either taken back into neuron for reuse or into glial cell to be cleared from synaptic cleft and terminate its action on postsynaptic neuron, both of these paths require ___ aka GAT pushing Na+ out to take GABA in

3 classes of GABA receptors

• GABA a

• GABA b

• GABA c

GABAa, GABAc

ionotropic GABA receptors only permeable to chloride that have a fast action on postsynaptic cells

GABAb

metabotropic GABA receptor, widely distributed in the brain, also inhibitory, usually activate K+ channels but also associated with others

dendrites, spines

glutamate receptors tend to be on the ___ especially on the ___

cell soma

GABA receptors tend to be near or on the __ which gives them a high influence on the cell’s action potentials

die

without GABA inhibition, neurons would fire action potentials continuously under influence of glutamate and eventually would __

benzodiazepines

ex: valium

increase binding of GABA

tranquilizing activity/reduce anxiety

barbituates

ex: phenobarbital

hypnotic drugs

useful in treatment of epilepsy, anesthesia

stabilizes neuron against excitation associated with seizures activity without sedating by increasing chloride flow

alcohol

inhibition of ionotropic GABA receptors

4

GABA receptor made out of __ subunits: 1 alpha, 2 beta, and 1 gamma.