Case 7 Flashcards
what is the major efferent neurotransmitter of the peripheral nervous system?
Ach - found at the neuromuscular junction, preganglionic autonomic synapses, and postganglionic parasympathetic synapses.
• ACh serves as a transmitter at synapses in the ganglia of the visceral motor system, and at a variety of sites within the CNS, especially in the basal nucleus of Meynert.
how and where is acetylcholine synthesised?
Acetylcholine is synthesized in nerve terminals from the precursors acetyl coenzyme A and choline, in a reaction catalyzed by choline acetyltransferase (CAT).
how and where is ACh hydrolysed? what takes up choline?
Ach is hydrolyzed by acetylcholinesterase (AChE) at the synaptic cleft into acetate & choline. Choline is taken up into cholinergic neurons by a high-affinity Na+/choline transporter.
what are the two types of ACh receptors?
- Nicotinic ACh receptor (nAChR) are nonselective cation channels that generate excitatory postsynaptic responses – found at the ganglion between pre- and postganglionic nerve.
- Muscarinic ACh receptors (mAChRs) are metabotropic and mediate most of the effects of ACh in brain. Muscarinic ACh receptors are highly expressed in the striatum and various other forebrain regions – found at the presynaptic membranes after the postganglionic nerve.
The main difference between the two is their MOA, one uses Ions (Nicotinic) and one uses G-Proteins (Muscarinic). Nicotinic receptors are all exciatory, while Muscarinic receptors can be both excitatory and inhibitory depending on the subtype. Another difference being where they are found on the body. (Sympathetic vs Parasympathetic Nervous System)
You find Muscarinic Receptors in the brain, heart, smooth muscle, or in the Parasympathetic nervous system. While Nicotinic Receptors are found in the Sympathetic nervous system, Muscarinic receptors are not. This is the crucial difference.
most excitatory neurones in the CNS are what?
glutamatergic
what happens with elevated concentrations of extracellular glutamate, released as a result of neural injury?
toxic to neurones
does glutamate cross the blood-brain barrier? what does this mean?
no
- therefore it must be synthesised in neurones from local precursors, either from glucose or glutamine
- glutamine is released by glial cells
- once released, glutamine is taken up into presynaptic terminals and metaboliesd to glutamate by the mitochondrial enzyme glutaminase
what happens to glutamate in the synaptic cleft?
- it’s taken up by glial cells and converted into glutamine by the enzyme glutamine synthetase
- glutamine is then transported out of the glial cells and into nerve terminals
what do all the ionotropic glutamate receptors generate? give examples for the receptors
(NMDA, AMPA, and kainate)
generate excitatory postsynaptic responses allowing the passage of Na+, K+ and Ca2+.
EPSPs produced by NMDA receptors can increase the concentration of what within the postsynaptic neurone?
the Ca2+ concentration change can then act as a second messenger to activate intracellular signaling cascades.
at hyperpolarised membrane potentials, what blocks the pore of the NMDA receptor channel? what changes this?
• At hyperpolarized membrane potentials, Mg2+ blocks the pore of the NMDA receptor channel.
• Depolarization, however, pushes Mg2+ out of the pore, allowing other cations to flow.
The opening of this receptor requires glycine
most glutamatergic synapses possess what receptors?
both AMPA and NMDA
The synaptic currents produced by NMDA receptors are slower and longer-lasting than the those produced by AMPA/kainate receptors.
what does activation of metabotropic glutamate receptors lead to?
• Metabotropic glutamate receptor (mGluRs) - Activation of many of these receptors leads to inhibition of postsynaptic Ca2+ and Na+ channels.
mGluRs cause slower postsynaptic responses that can either increase or decrease the excitability of postsynaptic cells.
what do most inhibitory synapses in the brain and spinal cord use as neurotransmitters?
γ-aminobutyric acid (GABA) or glycine
what is GABA formed from? and how?
glutamate
The enzyme glutamic acid decarboxylase (GAD), which is found almost exclusively in GABAergic neurons, catalyzes the conversion of glutamate to GABA.
in which system is GABA abundant?
the nigrostriatal system
what is most GABA eventually converted to? what does inhibition of GABA breakdown cause?
succinate by GABA transaminase
• Inhibition of GABA breakdown causes a rise in tissue GABA content and an increase in the activity of inhibitory neurons.
what are the different types of GABA receptors? how do each work?
- GABAA and GABAC (GABAc is found in the retina) receptors are ionotropic receptors.
- GABAB receptors are metabotropic receptors.
- The ionotropic GABA receptors are usually inhibitory because their associated channels are permeable to Cl-.
- GABA binds to a binding pocket between the α and β subunits, causing Cl- ions to flow into the neuron, leading to a decreased chance of action potential (hyperpolarisation).
- GABAB receptors are inhibitory due to the activation of K+ channels and inhibition of Ca2+ channels which tends to hyperpolarize postsynaptic cells.
where is glycine abundant?
in the spinal cord grey matter of the ventral horn
what is dopamine?
a catecholamine derived from dopa that functions as a neurotransmitter
what does dopamine act on?
acts on specific dopamine receptors and also on adrenoreceptors throughout the body, especially in the limbic system and extrapyramidal system of the brain as well as the arteries of the heart.
describe how dopamine is produced, released, take up, and broken down
- Dopamine is produced by the action of DOPA decarboxlyase on L-DOPA.
- Following its synthesis in the cytoplasm of presynaptic terminals, dopamine is loaded into synaptic vesicles via a vesicular monoamine transporter (VMAT).
- Dopamine action in the synaptic cleft is terminated by reuptake of dopamine into nerve terminals or surrounding glial cells by a Na+-dependent dopamine transporter, termed DAT.
- The two major enzymes involved in the catabolism of dopamine are monoamine oxidase (MAO) and catechol O-methyltransferase (COMT).
- Both neurons and glia contain mitochondrial MAO and cytoplasmic COMT.
how does cocaine produce its psychotrpoic effect?
by binding to and inhibiting DAT, yielding a net increase in dopamine release
what gives rise to the dopaminergic system?
two structures of the mid brain give rise to the system:
- substantia nigra
- ventral tegmental area