Exam 1 Flashcards
what is a neuron?
a cell that detects and responds to stimuli to send information over a long distance
what is a neuroglia?
it is a cell that protects, repairs, and assists neurons
what was the original 1839 cell theory?
that all organisms are composed of one or more cell, the cells are the basic units of structure, and all cells arise from pre-existing cells
(disproven) what was the reticular theory?
that all nerve cells were connected and formed a continuous network
what is a unipolar cell
one who’s dendrites and axons come out of one side of the cell body, the dendrites eventually separating from the axon
what is a bipolar cell
a cell who has two ends, one side has an axon, one side has a dendrite
what is a pseudo-unipolar cell
where the cell body comes off the side of the axon, where the axon goes in both directions, and on one end the axon becomes a dendrite
what is a multipolar cell?
where an axon comes out of one side, and dendrites come out from all kinds of directions
afferent vs. efferent
afferent: info towards the brain (sensory neurons)
efferent: info away from the brain (motor neurons)
neural circuits
(convergent excitation, divergent excitation, feedforward excitation, feedback excitation, recurrent (lateral) excitation, lateral inhibition, disinhibition)
write out and check against image in review
how does a knee jerk reaction work?
- a mallet hits the knee
- the extensor muscle sends a signal to the brain via the sensory afferent neuron
- the sensory neuron sends excitatory messages to an inhibitory interneuron which inhibits the efferent flexor motor neuron, but it sends excitatory messages to the efferent extensor muscle neuron
- this causes the leg to swing forwardw
what is an oligodendrocyte?
it facilitates greater conduction across axons, especially between the nodes of ranviar by myelinating axons
what is a schwann cell?
it is the oligodendrocyte of the peripheral nervous system, and does the same thing but not in the central nervous system
what is a microglia?
an immune cell that removes damage and debris (macrophage)
what is an astrocyte?
they regulate the BBB and create strong K+ buffering, promoting synapse formation
what are glial stem cells?
cells that give rise to new glial neurons
what are types of electrical signals that can give rise to an action potential?
external stimulation (light, sound, pressure, etc.) – usually for sensory neurons
chemical stimulation (via neurotransmitters)
strong stimulation
what is voltage?
the difference in electrical charge between two places
(usually in reference to across a membrane)
what is current
the rate of flow of charged particles
what is resistance
the opposition to flow of charged particles
what can’t pass through a phospholipid bilayer?
polar molecules without active transport
how is the resting potential established and maintained at a neuron membrane?
ATPase pump, leak cells are equal in and out when at electrochemical equilibrium
what is the Nernst equation?
Eion = (58/z) log([x]out/[x]in)
z = the charge of the ion
[x] = ion concentration
what is the Goldman equation?
Vm = (Pk[K]out + Pna[Na]out + Pcl[Cl]in) / (Pk[K]in + Pna[Na]in + Pcl[Cl]out)
Pk = the permeability of that ion across the membrane
what is electrochemical equilibrium?
a balance between the concentration gradient that makes an ion want to diffuse across the membrane and the electrical gradient that stops the ion from leaving the cell
how to prove that increased permeability is responsible for the depolarization of the membrane?
put a neuron in a solution with varying levels of Na+ concentration
RESULT: find that the spike height of the action potential depends on how high the external Na+ concentration is
how does Ohm’s law explain the rush of Na+ ions into a cell during an action potential?
Ohm’s law is voltage = current * resistance
resistance is the inverse of conductance (which is just permeability) –> so permeability is the inverse of resistance
Therefore,
current = voltage * permeability
I(ion) = g(ion) * (Vm - E(ion))
g is conductance, I is current
so the rate that Na+ flows across the membrane is a product of its membrane permeability and electrochemical driving force
the sequence of an action potential
- Na+ ions enter the cell, causing it to depolarize
- voltage-gated ion channels open, causing Na+ to flood in
- the depolarization moves across the axon, and as it moves the voltage-gated sodium channels close and the K+ channels open (these channels stay open for longer, causing overshoot)
- all channels are closed and RMP is reestablished
*K+ channels are slower
how does the voltage clamp method work?
it shows the current required to hold a certain voltage (holds the membrane at a certain voltage and see how the cell responds)
when its held at highly positive voltages, there’s a high moment of Na+ conductance and longer increased concentrations of K+
which are faster, ion channels or active transporters?
ion channels, bc diffusing down concentration gradient. Ion channels are passive
why must active transporters always be working to maintain the membrane voltage?
- has to go back to normal after neural signaling
- there is continual leakage at rest, need ATPase pumps to respond accordingly
what are the gating mechanisms of ion channels?
- ligand gated
- temperature dependent
- g-protein signaling
- voltage gated
what is distinct at the structure of a Cl channel?
its a dimer (two molecules linked together) with two pores
how many genes are in each channel of a Na+, Ca2+, K+ and Cl- ion?
Na+, Ca2+, and K+ all have four
Cl- has two
what is cell-attached recording?
what: tight contact between pipette and membrane
use: allows accurate measurement of the current flowing through one of a few channels in the patch, can even sometimes just look at a single channel
what is whole cell recording?
what: tears a hole in membrane, where the cytoplasm is continuous with pipette interior (has strong suction to keep it in place)
use: allows the voltage of the cell to be measured of controlled
what is inside-out recording?
what: cuts a piece of membrane off at two points, exposes it to air
use: makes the inside cytoplasmic domain accessible, can see how the outside of the cell responds via pipette
what is outside-out recording?
what: tears off membrane at two points, then reattaches where the inside is facing the inside of the pipette
use: makes the extracellular domain accessible, can see how the inside of the cell responds via pipette
when will a voltage-gated ion channel open?
its more likely to open at higher voltages, but its also a probability
how does the selectivity filter select for K+ ions in K+ channels?
K+ ions are dehydrated when they pass through the filter and are pushed through by electrostatic repulsion
4 protein loops around poor line the walls, carbonyl groups on the poor interact with the unsolvated K+ ion, balancing energy requried to remove its hydration cell
why couldn’t a sodium ion travel through a K+ channel?
its too small and t/f energetically unfavorable
stages of a sodium channel
- closed
- open
- inactivating
- inactivated
- closed
*important note, it inactivates while the voltage is still depolarized, bc refactory period
how does the inactivation of the Na+ channel work?
- only 3 of the 4 sensing domains are required to open the Na+ channel
- the fourth Na+ channel is the slowest one and is tied to inactivation of the channel
why does the K+ channel take longer to open than the Na+ channel?
it requires all four voltage sensing domains to be activated, while Na+ only requires three
what are channelopathies?
neurological disease caused by altered ion channels
what is ataxia?
the loss of voluntary motor movement, caused by altered K+ channels and Ca2+ channels
what is optogenetics?
manipulating neural activity via light
- ChR2, NpHR, Arch
benefits of optogenetics
bidirectional (can hyperpolarize and depolarize)
ex. yellow light is inhibitory
what is the difference between a chemical and electrical synapse?
a chemical synapse is slower and the ap is spread to the postsynaptic neuron via neurotransmitters, whereas an electrical synapse is much faster and activated via connexon channels (a type of ion channel at the gap junction)
what is one of the few CNS spaces that utilizes electrical synapses?
hippocampal interneurons
connexon
- # subunits
- how it allows molecules to cross
- 6 subunits
- passive flow through gap junction, large pores that allow ions, ATP, and second messengers
general sequence of events at a chemical synapse
- neurotransmitters stored in vesicles
- an action potential invades the synaptic cleft
- the depolarization opens Ca2+ voltage-gated channels
- the invasion of Ca2+ causes the vesicles to fuse with the membrane
- neurotransmitters are released into the synaptic cleft via exocytosis
- the neurotransmitters send inhibitory or excitatory signals to post synaptic neuron
- neurotransmitters are reuptaken by a glial cell or by enzymatic degragation
- retrieval of vesicular membrane from plasma membrane
what is an end plate potential?
a chemically induced change in electrical voltage measured at the neuromuscular junction. an electrode is inserted at the endplate to see how the release of neurotransmitters at the presynaptic neuron affecs the postsynaptic neuron depolarization/ hyperpolarization
how did we discover that chemical transmission was a thing?
- heart experiment: put a heart in a solution and stimulated the vagus nerve electrically, whatever was around that heart went to another heart and caused the rate of beats to slow down, proving that there’s a physical substance excreted by the neurons (later discovered as acetylcholine)
- did electrophysical pictures that showed neurotransmitters in vesicle pockets
- recorded end plate potential of frog neuromuscular junction, found that stimulating the axon led to a post synaptic membrane potential, when the EPP exceeded threshold
proving MEPP occur spontaneously
when a cell is in a Ca2+ deprived bath, still have MEPP recorded, showing that its spontaneous
what is the relationship between a MEPP and EPP?
there is a direct 1:1 relationship, showing that a postsynaptic cell is directly stimulated via neurotransmitter vesicles (organized in quantals)
STUDY: following the stimulus by low Ca2+, the distribution of EPP is consistent with amplitudes of MEPP’s
why do we know that Ca2+ entry is required for transmitter release?
STUDY:
control (w Ca2+) vs. Ca2+ channel blocker
when the blocker is in place (cadmium), there is no post-synaptic membrane potential
in the control (with Na+ and K+ channels blocked, a depolarizing post-synaptic membrane potential is still recorded)
why is Ca2+ necessary and sufficient?
proved that it affects the postsynaptic potential
proved that in the absence of Ca2+ there is no postsynaptic potential
small molecule neurotransmitter vs. large dense core vesicles
small molecules are in small clear-core vesicles and only require low frequency stimulations and localized increase in Ca2+ concentration
large dense neuropeptide vesicles require high frequency stimulation and a more diffuse increase in Ca2+ concentration
what does SNARE proteins do?
SNARE is SNap REceptor
they help the vesicle dock and form a complex that sits the vesicle on the membrane
the complex is made of synaptobrevin, syntaxin, and SNAP-25
what does Synaptotagmin do?
entering Ca2+ binds to synaptotagmin that hands off the vesicle, leading to curvature of the membrane to bring them together
–> fusion of the membrane leads to exocytotic release of neurotransmitter
what are synapsins for?
holds the reserve pool together in preparation of release to membrane
what would happen without synapsin: vesicles wouldn’t be ready for release, unable to transfer ap across cleft, more improbably system
what is CaMKII for?
phosphorylates synapsin to help move vesicles from release poll to docking
what would happen without CaMKII: vesicles would be stuck in the reserve pool
what is syntaxin for?
is on the membrane, binds with synaptobrevin on the vesicle to faciliate docking
what would happen without syntaxin: vesicles couldn’t dock on membrane and release neurotransmitters
what does clathrin do?
coats membrane to allow for curvature, facilitating dynamin-induced separation of the membrane to replenish vesicles
what would happen without it: there would be insufficient replenishment of vesicles, bc couldn’t pull them from membrane
what does dynamin do?
constricts the neck of the membrane to replenish vesicle supply
what would happen without it: there would be insufficient replenishment of vesicles, bc couldn’t pull them from membrane
what does synaptobrevin do?
part of SNARE complex that facilitates docking
what would happen without synaptobrevin: the vesicle wouldn’t be able to dock and thus release neurotransmitters into membrane
which are t-SNARE?
syntaxin and SNAP-25
which are v-SNARE
Synaptobrevin
how does BoTX affect neurotransmitter release?
they cleave either SNAP-25, syntaxin, or synaptobrevin
(something about the docking/ releasing complex)
theories of endocytosis
“kiss and run” barely opens and closes again
clathrin mediated
bulk retrieval, only during high frequency release
what causes the end plate potential?
the opening of ligand-gated acetylcholine receptors
does the postsynaptic membrane potential affect the end plate current?
when the post synaptic potential is negative, an EPC makes it more negative, whereas when its positive, after a certain point the current reverses direction back to 0
this demonstrates the reverse potential
the action of a neurotransmitter drives the postsynaptic membrane potential towards Erev for the particular ion channel being activated
how to utilize Ohm’s law to find the reversal potential?
EPC = g * (Vm - Erev)
when EPC is 0, changes direction
g = ionic conductance of molecule
Erev = electrochemical driving force
when does the molecule have an outward and inward current on an amplitude graph of Erev?
above 0 its a strong outward current and below 0 is a strong inward current
is membrane potential the same thing as voltage?
yes
how does Erev of a particular ion affect the postsynaptic potential?
based on the potential of the postsynaptic neuron, the voltage is either driven up or down by the released ions, as they drive towards their Erev levels
when is a neurotransmitter excitatory?
when the channel being driven releases ions who’s Erev is above threshold
*a current that brings the PSMP to be more positive can still be inhibitory if its reversal potential is still below threshold
how do peptide neurotransmitters reach the synapse?
they’re synthesized in the cell body and transported via axonal transport
how are small-molecule transmitters synthesized?
enzymes for synapse are synthesized in the cell body and transported via axonal transport, synthesis happens at nerve terminals
what are ionotrophic receptors?
ligand-gated ion channels
what are metabotrophic receptors?
g-protein coupled receptor
GABA
category: amino acid
impact: inhibitory
receptors: ionotrophic (5 subunits), structure similar to nAcHRs
synthesis: formed from glumatate, removed from cleft by GABA transporter (GAT), VGAT facilitates entry into vesicles
where: local circuit interneurons
GABAaR
- structure: similar to nAChRs, heteropentameric
- inhibitory bc permeable to Cl- who’s Erev is below threshold
- too much GABA: coma
- too little GABA: seizures
- associated diseases: anxiety, mood disorders, epilepsy
glycine
category: amino acid
impact: inhibitory
receptors: ionotrophic
where: local circuit interneurons
glutamate
category: amino acid
impact: excitatory
other facts: nearly all excitatory neurons in the CNS are glutamatergic, does not cross BBB
receptors: ionotrophic (4 subunits), metabotrophic (7 subunits)
synthesis: glutamine synthesized with glutaminase locally at presynaptic terminals
glutamate receptors
(ionotrophic) AMPARs:
- large, fast EPSC (excitatory post synaptic current)
- permeable to Na+, K+
- ligand-binding domain is a “clamshell” that shuts and moves gate helices to open channel when glutamate is attached
- 4 subunits
(ionotrophic) NMDARs:
- slower EPSCs and last longer
- permeable to Ca2+ too
- also voltage gated by Mg2+, and when the membrane is depolarized Mg2+ moves from blocking the channel
- co-incident detector: ligand and voltage gated
- 4 subunits
(metabotrophic) glutamate receptors:
- 3 classes with varying physiological roles
- implicated in synaptic depression of mGluR signaling affecting Alzheimer’s disease
- venus flydrap domain inactive when glumatate not bound
what are biogenic amines?
synthesized from aa by removal of carboxyl group
serotonin (5HT)
category: biogenic amine
impact: sleep, wakefulness, emotions
associated disease: depression, anxiety, schizophrenia, ESPECIALLY psychosis
receptors: ionotrophic, metabotrophic (7 subunits)
histamine
category: biogenic amine
impact: (CNS) arousal and attention, (PNS) allergic response and inplammation
receptors: 4 types of metabotrophic receptors
dopamine
category: biogenic amine
impact: coordinate body movements
associated disease: drug abuse w motivation and reward, cocaine inhibit transport (DAT), loss of coordination-Parkinson’s, dopamine agonists treat schizophrenia, bd, psychosis
location: VTA/ NA
receptors: metabotrophic (7 subunits)
norepinephrine (noradrenaline)
category: biogenic amine
impact: attention, arousal, wakefulness, fight/ flight response (PNS)
location: CNS, locus coeruleus
receptors: metabotrophic (beta and alpha adrenergic receptors)
acetylcholine
Category: acetylcholine
Structure: acetyl CoA & choline
Release: neuromuscular junction
impact: excites skeletal muscles, inhibits cardiac muscles
Other facts: used as Alzheimer’s meds, promotes wakefulness
exocytosis: enters vesicles via VAChT
synthesis: broken down by acetylcholinerase in postsynaptic terminal, reuptake of choline via ChT, binds with acetyl in cell via choline acetyltransferase
acetylcholine receptor
nAChRs (ionotrophic)
- 5 subunits, 2 ACh binding sites, both in alpha and must be occupied
- gates twist leading to tilting of the transmembrane domains and causing gate to open
*wide pore, permeable to Na+ and K+
mAChRs (metabotrophic muscarinic AChR)
- 7 subunits
what is a purine?
neurotransmitter’s who’s synaptic vesicles contain ATP that is co-released w the NT
*ATP acts as an excitatory nt in motor and sensory neurons
ATP receptors
(ionotrophic)
- trimeric
- nonselective cation
- pain sensation
(metabotrophic)
- causes drowsiness (blocked by caffeine)
what are neuropeptides?
receptors: metabotrophic
impact: pain transmission(substance P), pain suppression(endorphin, enkephalins), suppresses appetite(CCK)
where: brain, spinal cord, digestive tract, some are hormones
what is substance P?
a neuropeptide
mediates pain tramsmission
what is endorphin?
neuropeptide
pain suppression
what is enkephalins?
neuropeptide
pain suppression
what is CCK nt?
neuropeptide
suppresses appetite
how do immature neurons vs mature neurons respond to GABA?
in immature neurons, GABA is excitatory because there Cl- channels are less functional so there is greater intracellular Cl- so the Erev is above threshold
there are more efficient Cl- transporters in mature neurons
what is endocrine signaling?
broadcasting over a radio station
(entire body-blood/slow)
what is paracrine signaling?
posting a flyer
(local effects-extracellular fluid)
what is neuronal signaling?
email/ phone call
(direct/ fast effects)
what is contact-dependent chemical signaling?
face-to-face conversation
when do neurotransmitters not require a protein receptor?
when they are lipid soluble
can there be signaling molecules that aren’t neurotransmitters?
yes, ex. gases such as nitric oxide
what are lipid soluble molecules?
steroids, noepinephrine
what is the difference between ionotrophic and metabotrophic receptors?
ionotrophic receptors mediate behavior as ligand gated ion channels while metabotrophic receptors modulate behavior as GPCRs
types of g protein coupled receptors
(7 TMs)
signaling via protein phosphorylation:
- kinases phosphorylate ATP
- phosphorylates ATP w protein kinase
signaling via GTP-binding protein:
- GDP removed and replaced by GTP
- includes heterotrimeric and monomeric G-proteins
Gs (stimulatory GPCR pathway)
- g-protein binds
- adenylyl cyclase
- cAMP
- PKA
- increase protein phosphorylation
Gi (inhibitory GPCRs)
- G-protein binds
- inhibits adenylyl cyclase
- inhibits cAMP
- inhibits PKA
- decreases protein phosphorylation
Gq GPCR’s
- phospholipase C
- DAG or IP3
- PKC or Ca2+ release
- increase in protein phosphorylation and activates calcium-binding proteins
breaking down Gq pathway
what is phospholipase C? an enzyme that hydrolyzes lipids in the plasma membrane (IP3 and DAG)
DAG and Ca2+ phosphorylate PKC
examples of Gs receptors
serotonin, histamine, beta adrenergic receptor(norepinephrine)
examples of Gq receptors
mGluR
examples of Gi receptors
vasopressin, 5HT1c, mAchR, Alpha2 adrenergic receptors (noepinephrine)
G-protein cycle
- resting state, receptor not bound to ligand
- ligand binds to GPCR, G-protein releases GDP and acquires GTP
- Ga and Gby subunits separate
- the two units separately affect effector proteins
- Ga subunit hydrolyzes the GDP w GAPs and becomes inactive when its bound to GDP
- subunits recombine and inactivate
how does cAMP activate PKA?
cAMP phosphorylates the substrates and activates cAMP
examples of kinases (phosphorylating substances)
PKC, PKA, cAMP
how does caffeine affect GPCRs?
increases HR, inhibits breakdown of cAMP, increases HR
– if cAMP is not broken down, it will continue to increase expression of PKA and excite
how does nicotine affect GPCRs?
stimulates norepinephrine, increases HR
how does beta blocker affect GPCRs?
inhibits beta 1 receptor, decreases HR
how does Ca2+ facilitate LTD?
via the Gq route, release of Ca2+ stimulates PKC to downregulate AMPA receptors, inducing exocytosis from the membrane
how does Ca2+ interact within the membrane?
many mechanisms to maintain low levels of Ca2+ (pumps)
- binds to calmodulin and Ca2+ and calmodulin complex activate CaMKII, a kinase, which helps it phosphorylate AMPA proteins
how is CREM activated?
convergence of multiple signaling pathways
1. GPCR leading to PKA
2. Ca2+ channel creating the Ca2+/calmoduline kinase IV
3. RTK creating MAP kinase along w Ca2+ channel
this leads to phosphorylation of the CREM protein within the nucleus, leading to transcription and translation and a new protein
what are enzyme coupled receptors?
- 1 TM
- assemble complexes
- important in cell survival and proliferation
how does an RTK receptor generally function?
- dimer molecule binds to RTK
- kinase activity is stimulated leading to phosphorylated tyrosines (active RTK)
- signaling proteins bind to the phosphorylated tyrosines
- the adaptor protein connects to a Ras activating protein which inactivates Ras by phosphorylating the attached GDP to GTP
2 types of RTKs
- Trk receptors, which are activated by neutrophin ligands which are secreted. these are short range compared to hormones but long range compared to eprhins
- Eph receptors, activated by ephrin ligands, transmembrane proteins.
3 pathways for Trk receptors
PI 3 kinase pathway
1. adapter protein
2. PI 3 kinase
3. Akt kinase
4. cell survival
ras pathway
1. GEF
2. ras
3. kinases
4. MAP kinase
5. neurite outgrowth and neuronal differentiation
PLC pathway
1. phospholipase C
2. IP3 or DAG
3. Ca2+ release or PKC
4. neutrite outgrowth and neuronal differentiation
why are Trks important for cell survival?
when neurotrophins bind, promotes NGF (nerve growth factor) to prevent cell death
EphB receptors
thought to regulate excitatory synapse development via regulation of actin polymerization
dendritic spines?
where proteins are localized to concentrate signaling molecules
what are the cell surface receptors?
- GPCRs
- enzyme-coupled
- ion channel-coupled
how was LTP discovered?
1973 STUDY, found that in vivo reserach on rabbits in hippocampus found that greater stimulation altered the later response (greater ESPC)
how is LTP molecularly formed?
when there is a strong influx of depolarization, at glutamatergic receptors there’s a great influx of glutamate, activating the AMPA and NMDA receptors especially, this activation leads to the downstream affects of NMDA, which is influx of Ca2+, Ca2+ binds with calmodulin and CamKII and helps transcribe more AMPA receptors
