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NPB 100 Midterm 1 study guide

Neurons vs. glial cells (astrocytes, oligodendrocytes, microglia)
Neuronal staining
Ion channels (gate, ion selectivity, conductance= permeability and concentration gradient
for ion)
Patch clamp- record currents flowing through channels
Inward current: net movement of positive charge into cell
Forces acting on ions in solution:
Electrical force F=zV
Chemical force (concentration gradient between inside and outside of cell)
I-V curve, reversal potential and equilibrium potential
Nernst equation for single ion: E=RT/zF (ln [ion]out/[ion]in)
At room temperature, monovalent cation: E= 58 log [ion]out/[ion]in
Resting membrane potential: must maintain electroneutrality and osmotic balance.
Model cell with ion channels specific to a given ion: equilibrium when electrical force =
chemical force (concentration gradient) for that ion
K+: if [K]in= 400, [K]out= 20, then EK= 58 log 20/400= 58 log[1/20]= -75 mV
Real cell: membrane potential deviates from Nernst potential for K, because some Na
flows into cell at rest
GHK equation: Vm =(RT/F) ln (pK [K+]o + pNa [Na+]o + pCl [Cl-]i) /(pk [K+]i + pNa
[Na+]i + pCl [Cl-]o)
Takes into account permeability p for each ion, as well as concentration gradients
At rest, pNa<< pK so K has dominant effect on membrane potential, but depolarized
somewhat by influx of Na. Cl- has relatively minor or no effect.
Sodium-potassium ATPase: maintains concentration gradients for K and Na (otherwise
Na will eventually flow into cell and K out of cell so gradients break down)
Ion channels & transporters
Ionotropic: nAChR as example: pentameric structure, ion channel selectivity, mechanism
of channel opening when Ach binds alpha subunits
Voltage-gated: Na+, K+, Ca++
S4 segment= voltage sensor, pore loop= lining of channel
Mechanism of opening
Ion selectivity: determined by size of hydrated ion, or by ion that is dehydrated by
carbonyl groups lining selectivity filter of channel to allow the dehydrated ion (atom) to
pass through and rehydrate on other side
Ion transporters: most important is Na/K ATPase that takes 3 Na+ out of cell for every 2
K+ ions brought in= electrogenic, contributes up to -11 mV to membrane potential
Other transporters: Na+/Ca++
Cl- follows Na or K
Cl- -bicarbonate exchange
Action potential: rising phase due to Na+ influx through voltage-gated Na channels,
stopped by inactivation of Na+ channels, falling phase due to opening of voltage-gated K
Voltage clamp of squid giant axon (Hodgkin & Huxley): showed fast inward current
followed by delayed outward current
Inward current reduced with decreased external Na, and blocked by TTX
Outward current reduced by decreased intracellular K and blocked by TEA
I-V curve for voltage-sensitive K channels: outward current is fairly linear as function of
membrane potential when more depolarized than EK, reverses to inward current at
membrane potential more hyperpolarized than EK.

I-V curve for voltage-sensitive Na channels: complex. Inward current at membrane

potentials more positive than about -50 mV, inward current starts to decrease at +10 mV
and reverses to outward current at ENa.
Inactivation of voltage-sensitive Na channel: ball and chain (accounts for absolute
refractory period).
Action potential normally moves in one direction (from dendrites and cell body toward
nerve terminal) and cannot go backwards because of refractory period
Axon capable of conducting action potentials in either direction
Myelin speeds up conduction because action potential jumps from one node of Ranvier
to the next (saltatory conduction). Current of action potential flows along a very lowresistance
pathway of the axoplasm, with little current leaving the axon due to high
resistance of membrane and surrounding myelin sheath.
Electrical (RC circuit) and hose models of neuron
When no voltage-sensitive channels are in membrane, voltage changes spread passively
or electrotonically across membrane.
Time constant (tau): if a depolarizing current is injected into the neuron instantaneously,
the membrane potential does not change immediately but takes time to depolarize due to
charging of membrane capacitance Cm. Tau= RmCm (membrane resistance x
Space constant lambda: if a depolarizing current is injected into the neuron
instantaneously, the voltage recorded at varying distances from the site of maximum
voltage drops off as a function of lambda. Lambda= square root of Rm/Ri (membrane
resistance divided by intracellular resistance).
Cable equation combines time and space constants to describe the dropoff of a membrane
voltage as functions of time and distance along the membrane.
Neurotransmitter release
Squid giant synapse: record postsynaptic response as bioassay of presynaptic release of
Neurotransmitter release requires depolarization of presynaptic terminal, which opens
voltage-sensitive Ca++ channels. Depolarization and presence of Ca++ inside
presynaptic terminal are necessary for transmitter release.
Quantal release: in low-Ca++ medium, transmitter is released in a minimal size
(quantum) that evokes a postsynaptic response of 0.4 mV. Less frequently, stimulation
evokes postsynaptic responses that are some multiple of 0.4 mV.
Katz: recorded spontaneous miniature end plate potentials (sMEPPs) and found that they
were the same size as the minimum evoked response of 0.4 mV. Cannot be attributed to
the action of a single molecule of neurotransmitter, since size of sMEPP changes with
drug treatments.
Vesicular theory: neurotransmitter is packaged in synaptic vesicles in presynaptic nerve
terminal. Vesicles are lined up and docked at presynaptic membrane close to voltagesensitive
Ca++ channels.
Can visualize vesicles undergoing exocytosis (craters in freeze-fractured synaptic
membranes). Number of craters varied linearly with amount of neurotransmitter release
evoked by increasing concentrations of 4-AP.
Vesicular release evokes postsynaptic response of 0.4 mV, which is 1,000 times greater
than response of 0.4 V evoked by neurotransmitter binding to a single receptor to open
one ion channel.
Exocytosis: synaptic vesicles are docked at presynaptic membrane by complementary
docking proteins (synaptotagmin and synaptobrevin in vesicle membrane, SNAP-25 and
syntaxin in terminal membrane) to form SNARE complex

Depolarization of terminal opens voltage-sensitive Ca++ channels. Ca++ promotes

exocytosis by helping to form fusion pore (hole in vesicle and terminal membrane)
through which neurotransmitter diffuses out into synaptic cleft.
Bo-tox: prevents release of neurotransmitter from motor nerve endings by cleaving
docking proteins, so vesicles are no longer docked and ready to release.
After exocytosis, synaptic vesicle membrane is recaptured by endocytosis and re-formed
back into vesicles that can be reused.
At some synapses, vesicles may undergo limited exocytosis (not full collapse fusion) and
only release a portion of their contents: kiss and run
Synaptic transmission
Electrical synapses have gap junctions formed by connexons (connexin hexemer), which
allow current to flow directly from pre- to postsynaptic cell and also allow small
molecules to diffuse through. Electrical synapses less common than chemical in adults.
Chick ciliary ganglion has both electrical and chemical synapse. Electrical response is
recorded first at short latency, and chemically-evoked response a few milliseconds later.
Postsynaptic receptors are organized in a complex extracellular matrix with anchors to
intracellular cytoskeleton.
Direct transmission: ionotropic receptors.
Example: nicotinic acetylcholine receptor. Presynaptic stimulation evokes EPSP
(excitatory postsynaptic potential) with reversal potential at around 0 mV, meaning that
channel is non-selective and allows Na and K to pass through.
GABA is usually an inhibitory neurotransmitter, that binds to GABA-A receptor to open
a channel that hyperpolarizes postsynaptic cell (inhibitory postsynaptic potential)
Presynaptic inhibition at axo-axonic synapse: inhibitory neurotransmitter acting at
presynaptic terminal opens ion channels that prevent the incoming action potential from
depolarizing the presynaptic terminal, thus preventing transmitter release.
Indirect synaptic transmission by metabotropic G-protein-coupled receptors.
7-membrane-spanning segments with intracellular domain for G-protein binding and
extracellular domain to bind neurotransmitter.
Neurotransmitter binds receptor to activate G-protein, which can either directly affect
nearby G-protein-sensitive ion channels, or can interact with another effector (such as an
enzyme) to change levels of an intracellular messenger that interacts with ion channels.
Example 1: when acetylcholine binds muscarinic acetylcholine receptor, activated Gprotein
binds to K+ channel to hyperpolarize cell
Example 2: norepinephrine binding to beta-adrenergic receptor activates G-protein that in
turn activates adenyl cyclase to increase cAMP, which activates protein kinase to
phosphorylate voltage-sensitive Ca++ channels making them available to open and
depolarize the cell.
Many other examples were shown (but dont need to be memorized)
Effects of metabotropic receptors are slower, longer-lasting, and amplified.
Synaptic integration
At an active synapse, several presynaptic action potentials evoked EPSPs that piggyback
on top of each other to make it larger: temporal summation
EPSPs arriving at spatially separate synapses on a cell, and arriving at the axon hillock at
the same time, are summed: spatial summation.
EPSPs and IPSPs arriving at the axon hillock at any given moment are summed; if the
membrane is depolarized above threshold for voltage-sensitive Na+ channels an action
potential will fire.
GABA: ionotropic (GABA-A, C) and metabotropic (GABA-B)
GABA is most common inhibitory neurotransmitter (also glycine).
GABA is synthesized in presynaptic terminal from glutamate by glutamic acid

Once released, GABA is taken back into presynaptic terminal by GABA transporter
GABA-A receptors have benzodiazepine (tranquilizer) and barbiturate (anesthetic)
binding sites and are mainly involved in CNS inhibition by increasing Cl- current.
Glutamate is most common excitatory neurotransmitter in CNS.
3 different ionotropic receptors (AMPA, NMDA, kainate) and 8 metabotropic (mGluR18).
Glutamate is freely available and can be synthesized in presynaptic terminal from
glutamine via glutaminase.
Once released, glutamate is taken back up into glial cells or presynaptic terminal by
excitatory amino acid transporter.
NMDA receptor: has Mg++ blocking channel, so receptor requires both binding of
glutamate and certain amount of postsynaptic depolarization to expel Mg++ block to
open channel, which allows Ca++ influx.
Biogenic amines:
Norepinephrine: made by groups of cells in brain stem that have widespread projections
to entire CNS, often having an excitatory effect such as arousal, attention.
Serotonin: made by groups of neurons in midline brain stem areas with widespread
projections throughout CNS. Modulation of mood, sleep-wake cycles, perception.
Sometimes inhibitory but can also be excitatory.
Dopamine: made by neurons in substantia nigra and ventral tegmental area, with
projections to basal ganglia (involved in motor control and damaged in Parkinsons
disease), nucleus accumbens (drug addiction) and prefrontal cortex.
Acetylcholine: besides being the main transmitter at the neuromuscular junction, it is also
made by neurons in basal nucleus and other areas with widespread cortical projections.
Loss of cholinergic neurons in Alzheimers disease.
Neuropeptides: many exist, including brain-gut peptides (substance P, CCK, VIP), opioid
peptides (enkephalins and endorphins), and pituitary and hypothalamic releasing peptides.
Enkephalins: presynaptically inhibit transmission from nociceptor (pain-transmitting)
nerve terminals that synapse with spinal cord neurons.