Pharmacology Ch 7 82-92
Cellular Excitability
Excitability – ability of a cell to generate and propagate action potentials
-action potentials can propagate over several meters
-exciting a small cell can cause increase in intracellular ions to cause rapid release of chemical
transmitters to travel to receptors
Ohm’s Law – I (current) = voltage/resistance; I = V/R
Current = conductance * voltage; I = gV
-voltage across membrane is expressed as difference between intracellular and extracellular
potentials; V is negative when cell is at rest
-membrane is hyperpolarized when V is negative at rest and depolarized when V is more
positive at rest
-current defined with respect to direction of positive ion flow (Cl ions going inside is outward
current)
Ion Channels – method of current flow through a membrane; lipid bilayer acts as capacitor by
separating extracellular and intracellular ions. Magnitude of overall conductance dependent on
fraction of channels in open state and the conductance of channels in the open state
Resting Potential – is measured between -60 to -80mV and depends on 3 factors:
1. an unequal distribution of (+) and (-) charges on each side of membrane
2. difference in selective permeabilities of membrane to cations and anions
3. current-generating action of active and passive pumps to control gradients
-if K is the only ion in the cell, a chemical gradient is formed and K ions will want to flow outward
because there are more K ions inside the cell than outside
-if an anion A is also present, it is unable to cross due to lack of membrane channels, so
whenever a K+ leaves the cell, it separates the charges across the membrane
-establishment of negative membrane potential causes an electrostatic force that eventually
prevents net K efflux and starts to pull K back inside
-opposite forces: electrical gradient favors inward flow of K, chemical gradient favors
outward flow of K; forces combine to create electrochemical gradient
-transmembrane electrochemical gradient is the driving force for ion movement in membranes
Nernst Equation – Vx = (RT/zF) ln [Xout]/[Xin]; (RT/zF) is a constant
-electrogenic transport – pumps that govern concentration of net current by moving charge
-whenever an ion selective channel opens, membrane potential shifts toward Nernst potential
for that ion
Goldman Equation – determines resting membrane potential according to concentrations and
permeabilities of ions on outside OVER the same on the inside times a constant
The Action Potential – passage of small amount of current across a cell membrane causes
voltage across the membrane to change, reaching a new steady-state value that is determined
by membrane’s resistance
-if stimulated potential is less than the threshold value then membrane voltage changes
smoothly and returns to its resting value when stimulating current is turned off
-if potential surpasses the threshold value, the voltage rises dramatically to +50mV called an
action potential
-in most neurons, balance between V-gated Na channels and K channels regulate AP
-key to the excitability of membrane is the voltage dependence of P0
-the more positive the voltage, the more Na channels are open, and more
hyperpolarized, the more closed they are
Two types of Potassium Channels exist – voltage-dependent “leak” channels and voltage-gated
“delayed rectifier” channels
Leak Channels -contribute to resting potential by remaining open throughout the negative
range of membrane potentials, so K current is slightly outward at all times to maintain resting
potential and help repolarize membrane
-depolarization causes small Na currents to counteract leaky K ions; small depolarization causes
a positive feedback loop that constitutes rising phase of AP
-AP occurs in response to any rapid depolarization beyond Vt (threshold potential)
Delayed-Rectifier K Channels – contribute to rapid REPOLARIZATION phase of AP; these
channels open and close more slowly than Na channels in response to depolarization
-therefore, Na channels predominate early during depolarization phase, and outward K current
dominates later in repolarization phase
-final feature in determining membrane excitability is limited duration of Na channel opening in
response to membrane depolarization; after depolarization, most Na channels enter an
inactivated state; recovery from which only occurs during repolarization
-refractory period – lasts after AP until conditions of fast Na inactivation and slow K activation
have returned to resting values
Pharmacology of Ion Channels – local anesthetics injected locally to block Na channels in
peripheral and spinal neurons to inhibit AP propagation and prevents pain transmission
-drugs that block K channels are used to treat cardiac Arrhythmias
-Ca blockers treat hypertension by relaxing vascular smooth muscle to decrease resistance
-tetrodotoxin blocks voltage gates Na channels and inhibits AP propagation  paralysis
Electrochemical Transmission – nerve communication happens through neurotransmitters
-neurotransmitters synthesized by cytoplasmic enzymes and stored in vesicles (ACh, GABA,
glutamate, dopamine, and serotonin)
-most neurons specialized to secrete one type of neurotransmitter
-loading of neurotransmitters into vesicles is accomplished by ATP-dependent transporter
pumps that create an electrochemical gradient across membrane to fuel active transport
-when threshold voltage is reached in neuron, an AP is initiated and propagated along axonal
membrane to presynaptic terminal
-depolarization of nerve terminal causes opening of voltage dependent Ca channels and influx of
Ca which causes fusion of vesicles to presynaptic membrane and release into cleft
-neurotransmitter diffuses across the synaptic cleft where it binds to 2 classes of receptors in
postsynaptic membrane
1. ligand-gated ionotropic receptors causes ion flux across membrane leading to
excitatory or inhibitory postsynaptic potentials within milliseconds
2. metabotropic receptors – binding causes activation of intracellular 2nd messaging
system that can modulate ion function which leads to change in postsynaptic potential;
takes seconds to minutes
3. autoreceptors – on presynaptic membrane and can regulate neurotransmitter release
-EPSPs and IPSPs propagate passively along membrane of postsynaptic cell; all of these
summate and if exceed the Vt, an AP can be generated in postsynaptic cell
-stimulation is terminated by removal of neurotransmitter, desensitization of receptor, or both
- for G protein coupled metabotropic receptors, termination is dependent on intracellular
enzymes that inactivate second messengers
ACh – ACh diffuses across synapse and binds to ligand-gated ionotropic receptors in
postsynaptic muscle membrane which causes receptors to increase probability of opening ion
channels permeable to Na and K
-net inward current through open channels depolarizes muscle membrane
-end-plate potential is large but cannot stimulate an action potential, several EPSPs need to be
summated
Synaptic Vesicle Regulation – terminals contain 2 types of vesicles:
1. clear-core vesicles – store small organic neurotransmitter such as ACh, GABA, glycine,
and glutamate
2. dense-core vesicles – peptide or amine neurotransmitters; dense core vesicle release is
more likely to follow a train of imuplses (continuous or rhythmic stimulation as opposed
to a single AP)
3. clear core vesicles involved in rapid transmission, dense-core = slow transmission
-many proteins controlling vesicle trafficking have been identified
-Synapsin – has affinity for synaptic vesicles and also binds to actin; allowing it to link vesicles to
cytoskeleton at nerve terminals involved with cAMP and Ca/calmodulin
-these 2nd messengers control availability of synaptic vesicles for Ca-dependent exocytosis
SNAREs present in vesicle membrane and presynaptic membrane provide driving force for Ca
regulated and Ca independent exocytosis
-tetanus toxin and botulinum toxin act by selectively cleaving SNAREs to inhibit exocytosis
Postsynaptic Receptors – nicotinic ACh receptor and GABA receptors are ionotropic receptors
Transmitter Metabolism and Reuptake – two types of intervention involve inhibition of
neurotransmitter degradation and antagonism of transmitter reuptake
1. Acetylcholinesterase – degrades ACh, target for treatment of myasthenia gravis
-Cocaine – inhibits dopamine and norepinephrine reuptake in the brain
-Fluoxetine – inhibits serotonin-selective reuptake