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51: Neurotransmission/Neurochemistry

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What are some biological challenges that neurons have to overcome?
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– need to extend long processes – need to conduct signals over long distances – need to convey information in a polarized unidirectional manner (from sensory to motor components)
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What are some short-range signaling mechanisms used in the nervous system?
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– chemical synapses – autocrine signaling – paracrine signaling
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How does the nervous system achieve long-distance signaling?
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Humoral signaling
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What type of junction is used in the nervous system for electrical synapses?
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Gap Junctions
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What are the three basic types of cells used in the nervous system?
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Neurons Glial Cells Ependymal and endothelial cells
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What is the function of the glial cell?
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To support and maintain neurons
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What is an astrocyte and why are they important?
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A type of glial cell in the brain; major functions include holding the neurons together in proper spatial relationship and inducing the brain capillaries to form tight junctions important in the blood brain barrier. They also play a critical role in regulating metabolism.
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What are the two groups that make up acetylcholine?
What are the two groups that make up acetylcholine?
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– Ester – Ammonium group (permanently charged)
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What conformation does acetycholine prefer when in an aqueous solution?
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Gauche conformation (ester and ammonium only 60 degrees apart)
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What acetylcholine conformation is preferred for muscarinic binding?
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Trans conformation (ammonium and ester group are separated by 180 degrees)
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What is a cholinergic receptor?
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A receptor that is activated by acetylcholine.
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What are two types of cholinergic receptors?
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Nicotinic Muscarinic
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How do we differentiate between nicotinic and muscarinic receptors?
How do we differentiate between nicotinic and muscarinic receptors?
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Both are activated by ACh, but nicotinic receptors are ligand-gated channels that respond to nicotine and muscarinic are g-protein coupled receptors that respond to muscarine.
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What is a muscarinic antagonist?
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Atropine
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What are the two subtypes of nicotinic receptors?
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Nicotinic Muscle Nicotinic Neuronal
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What are the two types of nicotinic muscle receptors?
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– Nicotinic junctional (adult) – Nicotinic embryonic (downregulated after birth)
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Which subinit is different for all of the genetically different nicotinic neuronal receptors?
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alpha
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How many muscarinic receptors have been cloned and how do they differ from one another?
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There are 5 and they have different functions and are differentially expressed in tissues.
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What can be used to differentiate different cholinergic receptor subtypes?
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Drugs!
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What is an agonist for both nicotinic and muscarinic receptors?
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ACh
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What are two agonists for muscarinic receptors?
What are two agonists for muscarinic receptors?
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Muscarine Oxotremorine-M
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What is an agonist for nicotinic muscular receptors?
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Phenyltrimethylammonium Nicotine
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What is an agonist for nicotinic neuronal receptors?
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Nicotine 1, 1-Dimethyl-4-phenylpiperazinium
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What can muscular nicotinic receptors be inhibited by?
What can muscular nicotinic receptors be inhibited by?
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Tubocurarine Decamethonium
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What can neuronal nicotinic receptors be inhibited by?
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Trimethaphan Hexamethonium
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What are IPSP generated by?
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By catecholamines (e.g. dopamine, nor-epi) released by ACh acting on interneurons.
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Is neurotransmission by autonomic ganglia caused by a single transmitter? Why?
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No. There is a fast (initial) EPSP generated by ACh activating nAChR (latency <2msec). This is followed by a slow EPSP generated by ACh activating mAChR (latency ~1sec, duration 30-60 sec). Then there is a late, slow EPSP generated by neuropeptides activating respective GPCR (slow onset; duration several min). IPSPs are also generated by ACh interneuron release of catecholamines.
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What are some organs that are predominantly sensitive to sympathetic ganglionic blockade?
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Arterioles Veins Sweat glands
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What are some organs that are predominantly sensitive to parasympathetic ganglionic blockade?
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Heart Iris Ciliary muscle GI tract Urinary bladder Salivary glands
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What is the major receptor used by both the sympathetic and parasympathetic ganglia?
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nAChR for the production of the initial fast EPSP
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Where do muscarinic ACh receptors occur in higher densities?
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Postsynaptic effector sites (rather than autonomic ganglia).
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What does ganglionic blockade of the heart result in?
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Tachycardia due to the predominance of parasympathetic tone at the ganglia.
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What does ACh activation of the postsynaptic receptor of the heart result in?
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Bradycardia due decreased conduction (AV block at high doses), small negative inotropic action
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How does receptor subtype affect tissue response to postsynaptic stimulation by ACh?
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Activation of mAChRs can be excitatory or inhibitory depending on the receptor subtype and tissue affected.
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What is the predominant receptor at the neuromuscular junction?
What is the predominant receptor at the neuromuscular junction?
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nAChR, excitation-contraction coupling is fast.
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What enzyme is responsible for making ACh?
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ChAT (choline acetyltransferase)
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What is ACh made from?
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Choline and acetyl coenzyme A
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What limits ACh synthesis?
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Choline uptake into the presynaptic nerve terminal.
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What is the function of VAChT?
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To concentrate ACh (once synthesized) into presynaptic vesicles which is driven by a proton pumping ATPase.
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What are two sources of choline?
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– 50% recycled from hydrolyzed ACh – Breakdown of phosphatidylcholine
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How is ACh synthesis regulated?
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Through coregulation of ChAT and VAChT expression.
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What is a non-competitive vesicular ACh transporter (VAChT) inhibitor?
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Vesamicol
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What is a non-competitive choline acetyltransferase (ChAT) inhibitor?
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Hemicholinium
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How is ACh broken down?
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Breakdown needs to be rapid. This is done by AChE (acetylcholinesterase) at the synapse. ACh + water is broken down into choline + acetate +water. AChE has an anionic site that attracts the positive choline group. Makes serine in active site very active to promote breakdown.
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How many subunits make up the nAChR?
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5 subunits make up each of the 4 transmembrane segments (the alpha subunit is the only repeated one)
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What are the primary biochemical responses mediated by mAChR?
What are the primary biochemical responses mediated by mAChR?
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– Inhibition of adenylyl cyclase (decreased cytoplasmic cAMP with M2/M4) – Stimulation of phopholipase C (activation of PLC, DAG, IP3 –>cytoplasmic Ca2+, PKC activation) – Regulation of K+ channels (inhibition of adenyl cyclase and beta/gamma activation of GIRK)
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What does catechol refer to?
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A benzene ring with two -OH groups.
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What are some catecholamines that are derived from L-Tyrosine?
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– Dopamine (convert L-Tyrosine to L-DOPA via tyrosine hydroxylase; then L-DOPA to Dopamine via DOPA decarboxylase) – Norepinephrine (Dopamine to NE via dopamine beta-hydroxylase) – Epinephrine (NE to Epi via phenylethanolamine N-methyltransferase)
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What is the rate limiting step in catecholamine synthesis?
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Tyrosine hydroxylase hydroxylation of tyrosine at the meta position. This is highly regulated by phosphorylation (CaMKII, PKA, PKC).
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How is norepi degraded?
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NE is degraded by monoamine oxidase or catecholamine O-methyl transferase (COMT) to form MHPG or VMA that can be recycled to make more product.
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What are 3 important amine transporters?
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– Norepinephrine transporter (NET) – Dopamine transporter (DAT) – Vesicular membrane transporter (VMAT-2, takes them into vesicles)
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What is the function of vesicular monoamine transporter 2 (VMAT 2)?
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It is an integral membrane protein that transports monoamines (dopamine, NE, serotonin, histamine, etc) from the cellular cytosol into the synaptic vesicles.
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What determines which neurotransmitter will be put into the vesicle?
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The cell surface transporters like NET.
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Describe what happens during 5-HT (serotonin) and noradrenaline (NA) neurotransmission.
Describe what happens during 5-HT (serotonin) and noradrenaline (NA) neurotransmission.
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When a nerve impulse arrives at a 5-HT or NA nerve terminal the NT is released from the synaptic vesicle into the synaptic cleft. NT molecules bind to their specific receptors on the post-synaptic membrane and the nerve impulse is propagated or inhibited, depending of the receptor type. 5-HT and NA molecules are then released from their receptors and taken back into the nerve terminal via either the 5-HT or NA re-uptake transporters. 5-HT and NA are degraded by MAO and COMT, these enzymes are found in both the synaptic cleft and the nerve terminal.
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What happens when selective 5-HT and NA re-uptake inhibitors (SNRIs) are used? Why is this important in depression?
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Depression is associated with reduced levels of the monoamines in the brain, such as 5-HT. The selective 5-HT and NA re-uptake inhibitors (SNRIs) are thought to restore the levels of 5-HT and NA in the synaptic cleft by binding at their re-uptake transporters preventing the re-uptake and subsequent degradation of 5-HT and NA. This re-uptake blockade leads to the accumulation of monoamines in the synaptic cleft and the concentration returns to within the normal range. This action of SNRIs is thought to contribute to the alleviation of the symptoms of depression. In the presence of the SNRIs, small amounts of 5-HT and NA continue to be degraded in the synaptic cleft.
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Why do tricyclic antidepressants (TCAs) have side effects?
Why do tricyclic antidepressants (TCAs) have side effects?
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TCAs are non-selective inhibitors of amine re-uptake transporters that lead to dry mouth, blurred vision, constipation, urinary retention, and other effects due to off site effects on muscarinic receptors.