question

Definition of a NT

answer

1) Stored in a presynaptic vesicle 2) Released in a Ca-dependent manner 3) Capable of interacting with a membrane bound receptor to produce an effect

question

Definition of a neuromodulator

answer

Quite often meets all the requirements for a NT -Might have slower or long lasting effects than a true NT-- really properties of the downstream signalling cascades, not the transmitter itself -Or some aspect of the definition of a NT might be unclear -Just know that sometimes the definition is unclear.

question

Biosynthesis of AA derivative NTs

answer

CLEAR VESICLES Except ACh, the small molecule NTs are usually standard amino acids or derivatives -ENZYMES converting the AAs originate in nucleus -Post-translational modification in the cell body -Transported to terminals. At the terminals the NT biosynthetic reactions take place and packaged into vesicles -The AA precursors got into the neuron via uptake receptors on the terminal membrane

question

Biosynthesis of peptide NTs

answer

DENSE-CORE VESICLES -come from cleavage of larger peptide precursors within the RER and Golgi. -packaged 1st into vesicles and then transported down to the axon terminal.

question

Steps in presynaptic NT release

answer

1) AP depolarize presynaptic terminal 2) voltage gated Ca channels open and let Ca in 3) Fusion of vesicle with membrane -Postsynaptic response is directly proprotional to Ca conductance (Ga)

question

What did Ramon y Cajal prove?

answer

Neurons are individual cells

question

What did Loewi and Dale prove?

answer

ACh is a neurotransmitter. -Took 2 frogs hearts, stimulated vagus on one of them and it slowed down -Took the broth from that heart and bathed the second heart in it. -The other heart slowed down too, meaning there was something chemical in the broth that made it slow down. -due to hyperpolarizing effects of M2 mediated elevated K conductance. The BETA/GAMMA subunit is responsible for this, not the alpha subunit.

question

EPSPs and IPSPs usually involve which ions?

answer

EPSP usually involves elevated Na conductances IPSPs usually involve elevated K and Cl conductances -there are always exceptions to the rules

question

AP vs. EPSP or IPSP: which ones is graded?

answer

APs are not graded. They are all or none. -EPSPs or IPSPs can be graded. Increased activation from the presynaptic inputs yields larger post-synaptic potentials. -individual EPSPs are usually not enough to evoke an AP in the post-synaptic cell. They must be summated.

question

Synaptic delay

answer

Time between the pre-synaptic neuron being depolarized and the EPSP onset Things that happen during Synaptic Delay: 1) Ca enters pre-synaptic nuron 2) Vesicle release 3) Transmitter accumulation and diffusion across synapse 4) Binding and activation of post-synaptic receptors

question

Ionotropic vs. metabotropic transmission

answer

Ionotropic is usually fast -Metabotropic usually slow -Exception: GABAcR is ionotropic but slow -Fast or slow transmission is really a property of the receptor, not the NT

question

Examples of fast receptors

answer

Mostly ionotropic 1) nACh 2)glutamate (AMPA/kainate receptors) 3) GABA A (inhibitory) 4) glycine

question

Examples of slow receptors

answer

Mostly metabotropic w/ 2nd messengers 1) mACh 2) Metabotropic glutamate R 3) GABA B (inhibitory) 4) peptide transmitters (VIP, substance-P, enkephalin)

question

Presynaptic autoreceptors

answer

Type of axo-axonic receptor. -Autoreceptor on that same terminal does negative feedback to stop release of NT. Certain receptors in the following classes may do this: -DA -5HT -GABA

question

Presynaptic heteroreceptors

answer

Can also be axo-axonic. inhibits neuron that didn't originally produce the transmitter. -Examples: 5HT and Enkephalin

question

Strucutre of G-protein coupled receptors

answer

Ex: NTs (catecholamines, serotonin), Peptide hormones (glucagon), Rhodopsin (Opsin) -7 transmembrane domains -Single subunit receptor (Dimers in some cases) -Coupled through intracellular loop to heterotrimeric G proteins.

question

Mechanism of G-protein receptors

answer

-If no transmitter bound: alpha subunit stays bound to a GDP molecule -When NT binds, alpha subunit dissociates and binds GTP and goes off to start 2nd messenger cascade -Reset: alpha subunit has ATPase activity, NT dissociates from receptor

question

Which G-protein subunit confers specificity?

answer

alpha subunit (except M2)

question

Effect of Gs

answer

INCREASE adenylate cyclase

question

Gi

answer

DECREASE adnylate cyclase

question

Gq(p)

answer

INCREASE PLC

question

Go

answer

INCREASE K and Ca channels

question

Modes of g-protein operation

answer

1) affect ion channels (via g-gprotein, not directly) 2) start 2nd messenger system

question

Some second messengers

answer

1) cAMP 2) DAG 3) IP3 4) Ca

question

cAMP mechanism

answer

-Gs or G1 -cAMP from ATP by ADENYLYL CYCLASE -Target: -cyclic nucleotide-gated ion channels - PKA= cAMP-dependent protein kinase

question

Cyclic nucleotide gated channels (CNG)

answer

-conduct Na, K, Ca fairly non-selectively when bound by cGMP and cAMP -Belong to family of voltage-gated ion channels even though they show very little voltage dependence -Found in retinal photoreceptors and olfactory sensory neurons. (mutations can can retinal degeneration or color blindness.)

question

Achromatopsia

answer

Mutation in A and B subunits of CNG channel in retinal cones. -Causes color blindness

question

How does cAMP activate PKA?

answer

-PKA is a tetramer in inactive state -PKA regulatory subunits bind 4 molecules of cAMP and dissociate to expose catalytic subunits. -catalytic subunits phosphorylate many other kinds of proteins

question

Gp(q) mechanism

answer

Gq (p) activates PLC -PLC cleaves PIP2 into DAG and IP3 -DAG activates PKC -IP3 goes to ER to release Ca

question

Mechanism of Ca as a 2nd messenger

answer

-comes from: 1) voltage gated channels 2) NMDA receptors 3) Endoplasmic Reticulum (ER) Targets: -PKC -Calmodulin Ca/Calmodulin-dependent protein kinase (CaMK)

question

Calmodulin (CaM)

answer

-4 Ca binding sites per molecules -Complex of Ca and CaM regulates lots of enzymes like: -CaMK -Ca ATPase pump -Some subtypes of adenylyl cyclase and phosphodiesterases

question

Synaptotagmin

answer

Ca sensor for NT release

question

What are some substrates for neuronal protein kinases?

answer

1) Ion channels (K or Ca): modulate neuronal activity 2) Enzymes (Tyrosine hydroxylase): NT synthesis 3) Cytoskeletal proteins (Microtubule- associated proteins MAPs): Maintenence of neuronal structure 4) Transcription factors (cAMP response element binding protein CREB) : gene expression

question

Dopamine Receptors and biochem effects

answer

D1-5 1) D1 and D5: INCREASE Adenylyl cyclase 2) D2,3,4: DECREASE adenylyl cyclase

question

Norepineprine receptors and effects

answer

1) a1: INCREASE PLC 2) a2: DECREASE adenylyl cyclase 3) B: INCREASE Adenylyl cyclase

question

Acetylcholine receptors and effects

answer

1) Nicotinic: Na/K conductance 2) Muscarinic: -m1,3,5: INCREASE PLC -m2,4: DECREASE adenylyl cyclase and G protein coupling to ion channel. (M2 beta/gamma K channels responsible for frog heart experiment, and M2- alpha unit in heart can directly activate Ca channels under some conditions)

question

GABA receptors and effects

answer

1) GABAa: Cl conductance-- fast acting 2)GABAb:K conductance (g-protein coupled) could also do Ca conductance? 3)GABAc: Cl conducance --slow actin

question

Glutamate:

answer

1) AMPA/Kainate: Na/K conductance 2) NMDA: NA,K, Ca conductance. Has ligand and voltage gated properties 3) Metabotropic: INCREASE PLC

question

Agonist

answer

Any ligand that binds to a receptor and produces a physiological effect. Can include the endogenous or exogenous agonists

question

Partial agonist

answer

Binds same site but lower effect than the full agonist at an equimolar concentration

question

Inverse agonist

answer

Binds to the same receptor bu has action opposite to the antagonist

question

Competitive Antagonist

answer

Displaces agonist from binding site. Produces no physiological effects by itself.

question

Non-competitive antagonist

answer

Blocks action of the agonist at allosteric site. Doesn't prevent binding of agonist.

question

Allosteric modulators

answer

Substances that act at regulatory sites to change the binding affinity of the ligand. Usually induces conformational change to make the receptor more or less likely to bind ligand. Ex: Benzos enhance channel conductance whenever GABA molecules actually become bound to the site.

question

Synthesis of acetylcholine

answer

Catalyzed by CHOLINE ACETYLTRANSFERASE -Acetyl-CoA +Choline = acetylcholine

question

Degradation reaction of acetylcholine

answer

Catalyzed by acetylcholinesteras -Acetylcholine = Acetate and choline

question

Organophosphates

answer

Irreversible acetylcholinesterase inhibitors -Insecticides, biological warfare Symptoms: vasodilation, bradycardia, SLUD, bronchiolar constriction, miosis (pupillary constriction) convulsion, asphyxia. Antidote: Atropine (anticholinergic) Pralidoxime- facilitates cleavage of organophosphate from AChE at the esteric serine residue.

question

What enzyme packages ACh into vesicles?

answer

Vesicular ACh transporter

question

Nicotinic vs. Muscarinic ACh receptors

answer

Nicotinic: -Agonist: nicotine -Antag: Curare -Location: NMJ and brain -Ligand-gated ion channel -Fast EPSP (no IPSP) Muscarinic: -Agonist: Muscarine -Antag: Atropine -Location: Most prominent cholinergic receptor in brain --G1, Gp/q coupled ion channels. -Slow EPSP or slow IPSP

question

Synthesis of catecholamines

answer

1) Tyrosine --> L-DOPA (Tyrosine hydroxylase) --needs O2, Fe, pteridine cofactor. RATE LIMITING CYTOSOLIC ENZYME 2) L-DOPA--> Dopamine (DOPA Decarboxylase)-- needs pyridoxal phosphate. Cystolic enzyme 3) Dopamine--> Norepinephrine (Dopamine-B-hydroxylase)- needs O2 and Cu, located in synaptic granules 3) NE--> epinephrine (Phenylethanolamine-N-methyltrasnferase) needs S-adenosylmethionine. CYTOPLASMIC

question

Monoamine oxidase (MAO)

answer

NE and Epi use MAO-A DA can use MAO-A or B -Found in outer mitochondiral membrane of PRESYNAPTIC neuron. -Oxidative deamination of catechols into an ALDEHYDE AND AMMONIA.

question

COMT

answer

requires Mg. uses S-adenosyl methionine to add methyl group to catecholamine. -Usually found on POSTsynaptic membrane -Produces HVA, MHPG, VMA

question

Haloperidol MOA

answer

D2 receptor anatgonist

question

Reserpine MOA

answer

Antihypertensive, uncommon antipsychotic -blocks NT reuptake into vesicles

question

TCAs, MOA

answer

NE and 5HT reuptake inhibitor

question

Amphetamines MOA

answer

-May inhibit MAO? -DAT pump: Inhibits NE and DA reuptake into presynaptic neuron (actually pumps it out) -VMAT pump: Bumps NE and DA out of vesicles and increases their secretion into cleft. CAUTION CONCURRENT MAOI CAN CAUSE LETHAL HTN AND HYPERTHERMIA

question

Cocaine MOA

answer

Blocks DAT dopamine transporter at extracellular surface so more DA stays in synapse

question

Serotonin biosynthesis

answer

Tryptophan==5-hydroxytryptophan== 5HT via Tryptophan hydroxylase and aromatic L-AA Decarboxylase

question

Serotonin degradation

answer

MAO-A into 5-HIAA, which is excreted in urine.

question

Serotonin pharmacology

answer

-sleep, wakefulness -Pain, antinociceptive pathway

question

GABA biosynthesis

answer

Uses glutamic acid decarboxylase. -GABA is an AA with no role in intermediary metabolism

question

GABA degradation

answer

1) GABA-T (GABA transaminase) 2) SSADH (succinic semialdehyde dehydrogenase) End product: SUCCINIC ACID

question

What is the GABA shunt?

answer

When the neuron makes GABA, it has to use up an alpha-KG. The end breakdown product of GABA, succinic acid, can reenter the TCA cycle, but doesn't provide as much energy. TCA: 4 ATP (one was from GTP) GABA shunt: 3 ATP THE NEURON USES 1 ATP TO MAKE GABA!

question

GABA-A receptor

answer

Ionotropic Cl channel. -Benzos: not GABA agonist-- bind allosteric site to increase receptor affinity for GABA. EtOH, barbiturates, some steroids can do this too. -Other drugs: anesthetics, picrotoxins Anatagonist: BICUCULLINE

question

GABA-B receptor

answer

Metabotropic dimeric receptros. -One subunit has GABA binding site and the other has allosteric regulatory site -Coupled to K (and possibly Ca channels) via G proteins

question

GABA-C Receptors

answer

Ligand-gated Cl channels but with SLOW kinetics (compared to GABA-A -Not sensitive to barbs and benzos that characteristically affect the GABA-A channels

question

Glycine biosynthesis

answer

Not an essential AA -Made from serine via SERINE HYDROXYMETHYLTRANSFERASE plus pyridoxal phosphate

question

GABA vs Glycine

answer

1) GABA: from glutamate, prominent role in brain 2) Glycine: from serine, also inhibitory. Prominent role in spinal cord (Renshaw spinal interneurons) Ligand gated Cl channel, blocked by STRYCHNINE -Glycine can also modulate at glutamine synapses by interacting with the glutamate receptors, but this is unrelated to its actions as an inhibitory NT

question

Glutamate

answer

Major excitatory NT in brain -can be excitotoxic -Receptors: AMPA, Kainate, NMDA, Metabotropic mGluR1 to 5

question

NMDA receptor characteristics

answer

-Activates voltage gated ion channel gated by Mg -At rest the Mg sits in the pore because of electrostatic interaction. -If the Mg is sitting in the NMDA receptor, glutamate can't activate. (It can activate the AMPA receptor though) -NMDA receptor different from other glutR because it lets Ca through in addition to monovalent ions -NMDA regulated by GLYCINE

question

How does the NMDA receptor open?

answer

The AMPA channel has to open first -Strong depolarization of the postsynaptic membrane can eject the Mg from the pore. -If glutamate is still released during continued presynaptic firing, both AMPA and NMDA will be activated. This lets Ca through along with the monovalent ions into the postsynaptic membrane

question

Long Term Potentiation (LTP)

answer

Defined as "Long lasting increase in synaptic strength" -Activation of NMDA receptor essential for LTP -LTP associated with memory formation and associative learning, which has been best characterized in the hippocampus.

question

What is the basis for LTP?

answer

1) Influx of Ca through NMDA receptor channel 2) Ca-dependent processes in post-synaptic cell activated -CaMK and PKC activated, produce long term changes in the efficiency of the synapse 3) Increased numbers of AMPA receptors in the postsynaptic membrane 4) Phosphorylation (activation) of transcriptions factor like CREB to regulate gene transcription, incr expression of proteins that modify synaptic structure. =increased NUMBER AND EFFICACY OF AMPA CHANNELS

question

How do peptides interact with the nervous system?

answer

1) Neurosecretion 2) Regulation of Anterior Pituitary 3) Neurotransmitters

question

Neurosecretion

answer

Neuron makes peptide and stores it in vesicles at the axon terminal. -When stimulated, it releases peptides into BLOODSTREAM. (like Oxytocin and Vasopressin in posterior pituitary)

question

Regulation of Anterior Pituitary

answer

Hypothalamic releasing factors are all peptides except for one

question

Peptide neurotransmitters

answer

Can act as NTs in the CNS. The synthesis is different from classic NTs like acetylcholine. -Synthesis of peptide NTs occurs in neuronal cell body. Then it's processed and transported to the presynaptic terminal for vesicular storage and release.

question

Substance-P

answer

ID in 1931 on basis of ACh-like SM contraction -high concentrations in areas of pain regulation: 1) spinal cord 2)trigeminal nucleus 3)Hypothalamus 4) basal ganglia

question

How do we know substance P is a NT?

answer

Main evidence comes form role in primary sensory neurons -Located in DRG, neuron synapses on Dorsal horn neuron and goes to thalamus. -Ligation studies were done to block axonal transport to terminals within the spinal cord -Exogenous substance P applied to dorsal horn results in same effect as if you stimulated the DRG substance P neuron directly

question

How do we control pain via the substance P pathway?

answer

Serotonin neuron can turn on inhibitory enkephalin neuron to inhibit Substance P from DRG. -Sometimes the serotonin neuron can directly inhibit the substance P neuron

question

Classes of opiod peptides

answer

1)Enkephalins: Met and Leu enkephalins--pain inhibition 2) Beta-endorphin: for affective state, neuronal sensitivity, neuroendocrin regulation. Actually the most potent opiod in vivo, but probably due more to its stability and long half life 3) Dynorphins: from prodynorphin, selective for K-RECEPTOR. All over CNS esp hypothalamus, brainstem, spinal cord. Modulates pain, addiction, tolerance, withdrawal of cocaine. -In hypothalmus and pituitary help with homeostasis , appetite control, circadian rythems, temp regulation

question

How does dynoprhin mediate tolerance to cocain and depression?

answer

Activates PKA and CREB to elevate dynorphin expression in the nucleus accumbens, where it blocks DA release. this counteracts actions of cocaine and leads to tolerance. -Similar mechanism has been linked to depression.

question

Synthesis of beta-endorphin

answer

POMC in pituitary gland. Processing of POMC is tissue specific -Cleavage at basic amino acids into gammy liptropin and beta endorphin -(Alt cleavage of POMC can make ACTH) -Packaged into vesicle in trans-golgi. DENSE CORE -attached to neurotubules, moved by kinesin motor to axon terminal -vesicles transferred to actin neurofilaments for final transfer to active zones at synapse

question

Synthesis of Enkephalins

answer

From PROENKEPHALIN A -(there is a met-enk sequence within POMC, but there's no cleavage signal so you can't make it from POMC. There's no leu-enk in POMC at all. also met-enk is in pain area while beta endorphin is in hypothalamus) -Each proenkephalin makes 5 met-enk and 1 leu-enk

question

Synthesis of dynorphins

answer

From pro-dynorphin. -Can make dynoprhin A, B, AB, and alpha-neo-endorphin (total of 35 different peptides) -pro-dynorphin has parts of leu-enk, but none are cleaved to form it. -Prodynorphin mRNA is upregulated in rats after cocain administration

question

Characteristics of opiod receptors

answer

all are G-protein coupled -Inhibit Adenylate cyclase, increase hyperolarization through interaction with K channels -Decrease calcium influx through Ca channels -Basis of morphine pain path originating in dorsal horm

question

Naloxone

answer

competitive anatgonist -high affinity for MU receptor in CNS. (less K and D) -blockade= withdrawal symptoms, used in overdose

question

Naltrexone

answer

competitive antagonist -MU and KAPPA receptors (lesser extent delta) -manage opioid and EtOH addiction. -anatgonizes endogenous opioids like tetrahydropapaveroline, which has increase production when you drink alcohol

question

Delta receptor (OP1) d1, d2

answer

-analgesia, antidepressent, physical dependence 1) Pontine nuclei 2) amygdala 3)olfactory bulbs 4) deep cortex 5) peripheral sensory neurons

question

Kappa receptor (OP2) k1, k2, k3

answer

-analgesia, sedation, miosis, inhibit ADH release, dysphoria 1) hypothalamus 2) PAG 3) claustrum 4) spinal cord 5) substantia gelatinosa 6) peripheral sensory neurons

question

Mu receptors (OP3) m1, m2, m3

answer

Mu 1: analgesia, physical dependence Mu2: resp depression, miosis, euphoria, constipation, physical dependence Mu3: unknown 1) cortex (laminae III and IV) 2) thalamus 3) striosomes 4) PAG 5) spinal cord 6) substantia gelatinosa 7) peripheral sensory neurons 8) intestines

question

Nociception receptor (OP4)

answer

-anxiety, depression, appetitie, development of tolerance to Mu agonists 1) cortex 2) amygdala 3) septal nuclei 4) Habenula 5) hypothalamus 6) spinal cord

question

Describe mechanism of co-localization of small molecule NTs and peptide NTs

answer

-Can co-localize in same neuron for flexible signalling. -Small NTs release with low levels of firing and Ca, dense peptide vesicle release with more stimulation. might have to do with geometry of vesicular trafficking along cytoskeleton.

question

Parkinsons

answer

Loss of Da in nigral-striatal system

question

Schizophrenia

answer

Too much Da in mesolimbic and mesocortical systems

question

Alzheimer's disease

answer

No ACh in nucleus basalis

question

Huntington's chorea

answer

No GABA and ACh in striatum

question

Myasthenia gravis

answer

Autoimmune targeting AChR at NMJ (Gain of function)

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