Module 2 Lecture 4 Flashcards by Avery H

what is the principle subunit of Cav

alpha or alpha1 subunit (resemble the Nav alpha)

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what is the alpha/alpha1 subunit responsible for in Cav

gating and conduction

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what is the alpha subunit composed of in Cav

four repeat domains covalently linked together
- each domain has 6 TM sequences
- S4 = voltage sensor, S5 S6 = pore, w/ S5-S6 linker

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what are the ancillary subunits in Cav

alpha2-delta, beta, gamma

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what is alpha2-delta in Cav

two separate proteins (encoded by the same gene) - mostly extracellular, site of Gabapentin action
- traffcking and putting voltage-gated Ca channels in the right spot

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Gabapentin function

interferes and reduces amplitude of Ca current
- diminish neuronal activity

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beta subunit characteristics in Cav

intracellular & covalently bound to alpha, impacts voltage dependency

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gamma subunit characteristics in Cav

integral membrane protein; mostly found in muscle fibers

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characteristics of voltage-dependent peak Ca2+ current

similar to sodium but with Ca reversal potential

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how does voltage affect inactivation in Cav2.1

as voltage increases, inactivation becomes more likely

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role of glutamate in calcium channel

glutamate (E) amino acid residue lines each pore loop; form 4 pockets/binding sites w/ high affinity for Ca2+
- if another Ca2+ ion comes along, it pushes one through and occupies the binding site

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what did mutation of the P-loop glutamate (E) to alanine (A) do

decreased inward current during depolarization and reduced tail current

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what is the most diverse group of ion channels

potassium-selective channels

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characteristics of a functional K+ channel subunits

heteromultimeric assembly of alpha (pore-forming) subunits
- can be homotetramers or heterotetramers

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sources of K+ channel diversity

alternate mRNA splicing, post-translational modification, heteromultimeric association with modulatory subunits

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types of small-molecule neurotransmitters

acetylcholine, amino acids, biogenic amines

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types of amino acid neurotransmitters

glutamate, GABA, glycine

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types of catecholamines (biogenic amines)

dopamine, norepinephrine, epinephrine

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types of biogenic amines (not catecholamines)

serotonin, histamine

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when was ACh discovered

Vagus-stoff 1921, CNS action late 40s, early 50s

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when were adrenaline and noradrenaline discovered

mid 50s

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when was GABA (glycine) discovered

50s-60s

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when was glutamate discovered

70s, early 80s

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when was nitric oxide discovered

90s

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when were endo-cannabinoids discovered

early 00s

acetylcholine primary function

muscle control, memory formation, sensory response - excitatory

ACh locations

neuromuscular junctions, CNS

ACh receptors

nicotinic, muscarinic

serotonin primary function

intestinal movement control, mood regulation, appetite, sleep, muscle control

serotonin locations

gut, CNS

serotonin receptors

5-HT

dopamine function

reward pathways, cognition, voluntary motion

dopamine location

hypothalamus

dopamine receptors

D1, D2, D3, D4, D5

norepinephrine function

fight or flight response

norepinephrine locatino

adrenal medulla

norepinephrine receptors

andrenergic

L-DOPA function

precursor to dopamine

L-DOPA locatino

hypothalamus

tryptophan function

precursor to serotonin

tryptophan location

blood

GABA function

inhibits CNS

GABA location

brain

GABA receptors

GABAA, GABAB

glycine function

inhibits signals

glycine location

spinal cord, brainstem

glycine receptor

NMDA

tyramine function

blood pressure regulation

tyramine location

CNS, kidney

tyramine receptor

TA1

glutamate function

long term potentiation, memory

glutamate location

CNS, PNS

glutamate receptor

NMDA, others

2 major classes of transmission

- ionotropic (ligand-gated ion channels) - metabotropic (G-protein coupled receptors)

steps of ligand-gated ion channels

1. neurotransmitter binds 2. channel opens 3. ions flow across membrane

steps of GPCR

1. neurotransmitter binds 2. G-protein activated 3. G-protein subunits or intracellular messengers modulate ion channels 4. ion channel opens 5. ions flow across membrane

nACh receptor subunits

alpha 1-10, beta 1-4, gamma, delta, epsilon

AMPA receptor subunits

GluA1, GluA2, GluA3, GluA4

NMDA receptor subunits

GluN1, GluN2A, GluN2B, GluN2C, GluN3A, GluN3B

kainate receptor subunits

GluK1, GluK2, GluK3, GluK4, GluK5

GABA receptor subunits

alpha 1-6, beta1-3, gamma1-3, delta, epsilon, theta, ...

glycine receptor subunits

alpha1-6, beta

construction of native receptors

heterommultimers, but can be expressed as homomultimers in special circumstances - all of the ligand-gated subunits can function as part of the pore

alpha-bungarotoxin

known to induce paralysis and prevent neuronal activation of muscle

structure of Torpedo californica and Electrophorus electricus channels

- 5 subunit proteins - heteromeric or homomeric

characteristics of the nAChR subunits

native channels are heteromultimers of 5 subunits - each subunit has 4 TM domains (M1-M4)

what subunits do muscle nAChR channels express

alpha, beta, gamma, delta, and epsilon

what subunits do brain nAChR channels express

combinations of neuron-specific alpha and beta subunits

characteristics of alpha subunits in nAChR channels

have a cysteine loop for gating (member of Cys-Loop superfamily, along with glycine, GABAA, and 5-HT3)

what is the cysteine loop important for in the nAChR channel

binding of ACh and gating of the channel

is the nAChR mostly intracellular or extracellular

extracellular

what forms the nAChR pore

what happens upon ACh binding at two alpha subunit cysteine loops at 2 crucial tryptophan residues

M2 tilts and twists outward - this opens the pore and causes displacement/shifting of subunits (particularly beta subunits)

vestibule function in nAChR

contain negatively charged amino acids -- selecting for cations

what ions does nAChR generate

mixed current

why does nAChR generate a mixed current

pore is larger than of any voltage-dependent ion channels so far - when in the closed conformation, too narrow for fully hydrated ions, but no carbonyl backbone to replace hydration cage - when in the open conformation, accepts fully hydrated cations

how does signal to noise ration change throughout development

increases

what is the composition of nAChR early in development

lots of nAChRs composed of alpha, beta, delta, and gamma subunits - smaller single-channel conductance - slower gating (longer open)

what is the composition of nAChR as an adult

gamma subunit is replaced with epsilon - larger single-channel conductance - faster gating

what happens when you mutate the 3 rings of negative charges surrounding the pore

reduces conductance, but not selectivity

what ions does WT homomeric alpha 7 conduct

cations

what ions does WT GABAA R conduct

anions

what ions does mutated AChR conduct

aniona (switched 3 amino acid residues)

what do ligand gated AChR and GABAA - R have in common

- members of the Cys-loop superfamily - usually heteropentamers - M2 lines the pore - ring of negatively charged amino acids around the pore does not control cation/anion specificity

what does selectivity depend on in ligand gated AChR and GABAA - R

3 other amino acids within the pore region

subunits of GABAA

usually 2 alpha, 2 beta, and 1 gamma or delta subunit

what are the three gene families for ionotropic glutamate receptors

AMPA, NMDA, Kainate

characteristics of receptors in ionotropic glutamate receptors

- native receptors are heterotetramers - in expression systems certain receptors can function as homotetramers

AMPA receptor function

mediate the majority of fast excitatory transmission in the brain - usually heterotetramers with 2 GluA1 and 2 GluA2 subunits

NMDA receptor function

coincidence detectors - play a special role in synaptic plasticity

glutamate role in ionotropic glutamate receptors

agonist at all families - AMPA, NMDA, or Kainate are agonists only for their respective families

what are the three domains of the GluA1 subunit

- amino-terminal domain (ATD) - ligand-binding domain (LBD) - transmembrane domain (TMD) forms an asymmetrical Y-shaped protein

what are the transmembrane domains of the GluA1 subunit

M1-M4 TM regions

M2 characteristics in GluA1 subunit

p-loop, forms the pore

what are the sites for alternative splicing in GluA1 subunit

flip/flop (M3/M4 linker), and mRNA editing (Q/R - M2 and R/G - M3/M4)

what is the effect of binding of glutamate to LBD

causes the 'clamshell' orientation of the ATD and LBD to close, leading to movement of the gate and opening of the pore

ion selectivity of glutamate receptors

all glutamate receptors conduct Na+ and K+

NMDA receptor ion selectivity

Ca2+, Na+, and K+

AMPA receptor ion selectivity

do not conduct Ca2+ if the GluA2 subunit is present

what are the most common AMPA receptors

GluA1+2 and GluA2+3

conductivity for Ca2+/Na+, K+ in GluA1/GluA2

0.05

conductivity for Ca2+/Na+, K+ in GluA1

conductivity for Ca2+/Na+, K+ in GluN1/GluN2A

3-11

conductivity for Ca2+/Na+, K+ in GluN1/GluN2B

conductivity for Ca2+/Na+, K+ in GluN1/GluN2C

function of heterotetramers composed of GluA1, GluA3, and GluA4 subunits (GluA2-lacking AMPARs)

conduct Na+, K+, and Ca2+ - inwardly rectifying current - PCa2+/PNa = 1-3

function of heterotetramers composed of GluA1 and GluA2 subunits (GluA2-containing AMPARs)

conduct only Na+ and K+ - PCa2+/PNa = 0.001 - 0.005