Biology 3240 Intro Cellular Neurobiol, Fall '09
Key Words & Concepts: Lectures 33-40
This page will offer some key words and ideas from lectures, provided as rough study guides.
Larry Okun, Doju Yoshikami
(to Suggested Readings instead)
Lecture 33 11/20/09
examples of additional ion-channel types (most today V-sensitive, i.e. 'V-gated')
- named for currents through them
- e.g., could call 'classic' Hodgkin-Huxley (HH), V-sensitive Na+ and K+ channels in axons 'INa(HH)' and 'IK(HH)';
(members of larger families usually referred to as 'INav' and 'IKv' for V-sensitivity)
- discuss today ones named
IA (involved in AP frequency regulation)
IK(Ca) (a Ca++-activated K-channel involved in one type of 'adaptation' and modulated by NE)
Iir (an 'inward rectifier' promoting energy economy)
Ih (a 'hyperpolarization-activated' channel believed involved in 'pacemaking')
- also mention two V-sensitive ICa's and two 'slow' HH-like IK's of the heart AP
- and IK(ACh) - one of heart channels modulated by ACh
IA: control of AP frequency in response to steady depolarizing (stimulus) current
(Note: HH INa alone can produce a single AP with supra-threshold stimuluation --
since gNa will activate then inactivate, causing Vm to increase, then decrease.
But steady depolarizing current may produce only a single AP unless HH IK is also
present to 'pull' Vm back near its resting value (Vrest), despite the depolarizing current,
so that Na-inactivation can be removed, permitting a subsequent AP.)
- problem: HH INa, IK alone give nearly constant firing frequency over range of steady depolarizing currrents,
but at normal 'initiation sites' AP frequencies depend on stimulus strength
- IA common at sensory endings, neuronal cell bodies, where axonal APs initiated
- a K+ current (K+ channel), thus IA 'pulls' Vm towards VK
- rapidly activated by subthreshold depolarizations (small increases of Vm);
more slowly inactivated (rates of activation, inactivation similar to those of HH INa)
- while active, 'fights' depolarizing current, delaying approach to threshold and trigger of AP,
thus making AP frequency dependent on strength of stimulus current
- inactivation relieved only at Vm below Vrest, e.g., during AHP following an AP;
thus channel is 'reprimed' during each AHP, so regulates frequency of AP trains,
but doesn't delay first AP or add any K+ current at resting potentials;
IK(Ca): also regulates rates of AP trains; role in frequency 'adaptation'
- also a K+ channel, thus IK(Ca) pulls Vm toward VK
- activated by Ca++ that enters (through V-sensitive ICa channels) during APs
- can produce an additional, long-lasting AHP following an AP
- while active, 'fights' depolarizing current, further delaying trigger of APs,
- in an AP train additional Ca++ entry during successive APs can increase number of IK(Ca) channels open,
further 'fighting' initiation of new AP's,
thus slowing AP frequency, or even terminating AP train ('adaptation' of response to steady stimulus)
IK(Ca) is modulated in some neuronal cell bodies by transmitter NE:
- this NE effect via a G-coupled receptor, activating adenyl cyclase, increasing intracellular [cAMP],
in turn activating a protein kinase (PKA) which phosphorylates IK(Ca) channels, decreasing IK(Ca)
- 'cancels' adaptation, permitting sustained AP firing with steady stimulus
for Iir, Ih, consider APs of heart muscle
overview of heart structure, blood flow:
- from veins to right atrium, then to right ventricle, then to lungs;
- from lungs to left atrium, then to left ventricle, then out to arteries
- atria contract together, then ventricles together
heart rhythm, contraction sequence generated by muscle fibers themselves:
- gap junctions between muscle fibers communicate APs, synchronize parts
- special fibers initiate, coordinate contractions
- SA (sinoatrial) node in right atrium initiates beat;
activity communicated across atria by Bachmann's bundle and gap junctions;
atria insulated from ventricles, APs must pass through small, slow AV (atrioventricular)-node fibers,
then communicated to ventricles by Bundle of His (Purkinje fibers) and gap junctions;
first to apex of ventricals, then spread upward to 'base'
APs of heart muscle (vary somewhat among fiber types)
- all are very long, 200-400ms or more
- those of SA, AV nodes briefer, lack sharp peaks, longer plateaus of APs in atrial, ventricular cells
heart AP sequence and EKG:
EKG (potential differences detectable at skin from currents generated by large groups of cells)
'P,Q,R,S,T' waves, first described (and named) by Einthoven, ca. 1901, using his string galvanometer
- SA node AP (few cells involved, little effect on EKG)
- atrial AP onset -- EKG 'P' wave
- atrial AP plateau (small currents, little effect on EKG)
- AV node/Purkinje fiber APs (few cells involved, little effect on EKG)
- ventricular AP onset (slightly different times at apex and base: brief, strong currents) -- EKG 'QRS' complex
- ventricular AP plateau (small currents, little effect on EKG)
- ventricular AP reploarization (different times, different parts) -- EKG 'T' wave
- duration, start of P to to end of T, approx. 0.5 sec (500ms)
currents responsible for heart APs:
- AP initiated by:
- fast, V-sensitive INa (similar to HH INa), 1-2ms duration (inactivates),
producing brief 'overshooting' (positive) peak in APs of several fiber types
(this current, and overshooting peak not present in SA-node fibers)
- and V-sensitive 'transient' ICa,T, 20-50ms duration (inactivates),
activated at relatively low Vm, then inactivated by elevated Vm
- AP maintained by: second V-sensitive, 'long-lasting' ICa,L,
activated at higher Vm (once AP underway), producing long AP 'plateau'
(and contributing Ca++ to activate muscle contraction);
plateau phase can last 200-400ms or more, longer in ventricular than in atrial fibers
- AP terminated by:
- slow reduction of ICa,L plateau
by decrease of VCa, as [Ca++]i rises, contributing to slow decrease of Vm
and by some direct or indirect action of increased intracellular Ca++ on ICa,L channels, closing them
- and by two (very) slowly activated IK's (to 'fight' ICa,L),
both like HH IK, but activated much more slowly (~100-1000x) at high Vm:
IKr 'rapid' (for heart), activation time ∼150ms
IKs 'slow' (very!), full activation time > 3sec
IKr is especially unusual -- inactivation of it is faster than activation, so much of it is 'hidden'
(although activated) at high Vm, then 'revealed' (by fast relief of inactivation) when Vm decreases.
- and, finally, by more rapid closing of ICa,L channels and 'un-hiding' of activated IKr as Vm decreases,
ending the 'plateau' and producing a rapid return to low Vm
Iir: contributes to ion-current economy
- problem: heart APs long-lasting; strong ionic currents could tax concentration gradients,
would require more energy input for restorative pumps
- Iir channels -- 'resting' K+ channels that are open at low Vm, inactivated at elevated Vm;
thus Iir stops 'fighting' ICa currents during long APs;
(this, along with low numbers of ICa channels, reduces ionic currents during long heart APs;
in fact, total membrane conductance in these cells can be lower during the plateau phase than during 'resting' periods)
(Iir not prominent in pacemaker fibers, present in fibers with very long APs)
- an 'inward-rectifying' channel -- more K+ current passed (inward) at lower Vm, than (outward) at high Vm
some types of 'rectification' seen so far, all examples involving K+ channels:
- 'expected' concentration-dependent rectification:
easier outward current passage, from high [K+]i, than inward, from lower [K+]o
- 'delayed rectification' of HH IK:
much easier outward passage of K+ current at high Vm once V-sensitive IK channels opened
- 'inward rectification' of Iir:
channels are open at low Vm, allowing easier passage of inward K+ current,
are inactivated at higher Vm, preventing passage of outward K+ current;
direction of rectification opposite to that expected from K+ concentration difference,
thus also called 'anomalous' rectification
[mechanism is 'plugging' of these channels by intracellular cations (Mg++ or polyamines) when Vm raised;
part of this inactivation is rapid (< 1 ms.), part takes longer (few ms. to few hundred ms.)]
Ih: a 'pacemaker' current, hyperpolarization-dependent
- problem: heart muscle fibers (e.g., of SA node) must generate own rhythm, need own 'internal' stimulus current
- Ih channels -- members of K-channel family but also permeable to Na+,
have a Vreversal (∼ -30 to -20mV) well above Vrest, producing a depolarizing current if opened at lower Vm
(as do ACh-activated synaptic channels in skeletal muscle)
- only activated at low Vm, around (or below) Vrest -- hence 'hyperplarization-activated';
- inactivated (within about 100ms) at elevated Vm
generation of new heart-muscle AP after one has ended (the 'pacemaker' period):
- strong AHP generated by the 'slow' and 'very-slow' IK's that terminated first AP;
- these gK's almost only g's present; most other channels closed, thus Vm very near VK;
- these slow IK's also very slowly de-activated (channels close) at low Vm (over few 100ms);
- need some inward I to raise Vm, initiate new AP; this provided by:
- small 'background' INa
- and Ih, which becomes activated at low Vm, during AHP
- slow de-activation of IK, along with these two inward currents, produces slow depolarization,
eventually activating V-sensitive ICa,T, which raises Vm,
activating ICa,L and producing new AP in SA-node fibers
- Ih is inactivated at elevated Vm (so doesn't 'fight' AP once it has helped start it,
i.e., continuing Ih doesn't keep 'pulling' Vm back toward its Vreversal of -30 to -20mV)
Ih-type channels also present in neurons of mammalian brain (e.g., cortex, hippocampus),
seem likely to be involved in spontaneous firing of some neuronal classes
IK(ACh): a K-channel activated by by ACh, via G-coupled ACh receptor, apparently directly by G-protein subunit Gβγ
(in atria, SA-nodes, AV-nodes; not found in ventricles)
- when open, these channels (resting IK channels) 'fight' depolarization by Ih, etc., thus slowing heart rate
- this main effect responsible for heart slowing in Loewi's (1921) first demonstration of 'chemical transmission'
- IK(ACh) channels found to be another exaample of 'inward-rectifying' ones, inactivated at elevated Vm,
(thus not 'fighting' heart AP once started), basis of another name for them --
- these 'G-protein-activated, Inwardly-Rectifying, K+ channels, 'GIRK' channels;
differ from Iir inward-rectifier, 'IRK,' channels of non-pacemaker (long-plateau) cells
'orchestra' of channels critical for heart function; mutations in any of several known to cause fatal disorders
one example: 'Long QT' syndrome -- a 'channelopathy'
inherited defect
symptoms (children, young adults): EKG with 2-5% longer Q-to-T time in EKG
(delayed repolarization -- longer plateau -- of ventricular APs)
usually not serious,
but, with stress, can get severe arrythmia, uncontrolled contractions, incomplete ventricle filling;
less blood to brain (fainting), ventricular fibrillation, sudden death
genes discovered in families with disorder, most identified as ion channels of heart AP;
thus far reported examples involve mutations in proteins for INa, IKr, IKs, Iir, and ICa,L
further recent elaborations not menttioned in class:
IK(Na) (in some neurons): K+ channels activated by Na+ that enters during APs
- effects similar to those of IK(Ca) types
other roles suggested for Ih:
- e.g., unexpectedly found to be rich in neuronal dendrites; proposed to contribute a 'background'
depolarizing current that is reduced (inactivated or de-activated) when Vm is raised by a series
of excitatory synaptic potentials; removal of this depolarizing current reduces net deploarization,
suggested to 'stabilize' dendrite to excessive excitation by temporal summation of epsps
other 'pacemaking' currents (depolarizing ones at low, near-resting Vm):
- 'INa persistent' - resdiual INa at resting potentials
- 'INa resurgent' - current believed to result from a class of channels inactivated ('plugged')
while in an open (activated) state; current results at return to low Vm when plug
is removed (inactivation relieved), and just before channels can close ('de-activate')