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Bi/CNS 150 Lecture 1
Monday, September 30, 2013
The ionic basis of neuroscience;
Introduction to the course.
Henry Lester
H2O K+ ion
carbonyl
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Who are the Bi/CNS 150 students?
3 graduate students
Fields:2 Bi1 CNS4 CCE1 BE1 ME
Total undergraduate enrollment, 3812 seniors, 20 juniors, 5 sophomores, 1 freshman
Majors:20 Biology, 3 CNS, 6 BE, 2 Ch, 3 ChE2 Ph2 CS
Preliminary numbers
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What is the most abundant molecule in an organism?
Molecule Class Vote Comments
water
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Water is the most abundant molecule in an organism
H2O MW = 18Density ~ 1 kg/l
Therefore the concentration of water in an aqueous solution is ~ (1000 g/liter )/(18 g/mol) = 55 mol/liter or 55 M.
All other molecules in the body are at least 100 times less concentrated.
Therefore we need to understand the properties of water.
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Extracellular conc
Intracellular(Cytosol)
majormonovalent
Ions
Na+ 145 mM 15 mM
K+ 4 mM 150 mM
Cl- 110 mM 10 mM
divalentcations
Ca2+ 2 mM 10-8 M
Mg2+ 2 mM 0.5 mM
Other ionsPi
-2 2 mM 40 mM
H+ 10-7 M 10-7 M
Protein 0.2 mM 4 mM
Typical extracellular and cytosolic ion concentrations (mammalian cell)
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One clue to a cell’s ionic concentrations:Sea Water
Sea Water Extracellular conc
Intracellular(Cytosol)
majormonovalent
Ions
Na+ 457 mM 145 mM 15 mM
K+ 9.7 mM 4 mM 150 mM
Cl- 536 mM 110 mM 10 mM
divalentcations
Ca2+ 10 mM 2 mM 10-8 M
Mg2+ 56 mM 2 mM 0.5 mM
Other ionsPi
-2 0.7 mM 2 mM 40 mM
H+ 10-7 M 10-7 M 10-7 M
Protein 0.2 mM 4 mM
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Membranes provide a barrier to diffusion around cells,forming compartments
Alberts 4th 2-22© Garland
Little Alberts 12-1© Garland
. . . But specialized proteins (channels and transporters)
control the permeation of many molecules
natural or synthetic lipid bilayer
Alberts 4th 11-1© Garland
nicotine
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ExternalMonovalent cations:High Na+
Low K+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Internal:same asExternal
Na+
Na+
Na+
Na+
Na+
A Cell that Lacks Concentration Gradients
K+
K+
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ExternalMonovalent cations:High Na+
Low K+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
K+
Internal:Low Na+
High K+
K+
K+
K+
K+
Storing energy in a concentration gradient without osmotic stress:
Simply reverse the ratio of Na+ and K+
K+
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The “Na+ pump” splits ATP to make a Na+ and K+ concentration gradient
Alberts 4th 11-8 © Garland
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2
Alberts 4th 11-8 © Garland
From Kandel 6-5
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Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
K+
K+
K+
K+
Converting a concentration gradient to an electrical potential:
Create permeability to one ionic species (K+)
Lost positive charge leads to net negative interior potential
K+ channels
K+
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K+
K+
K+
K+
K+
The Nernst potential: the energy of discharging the concentration gradient for K+ ions
balances the energy of moving the K+ ions through the potential difference
Hundreds or thousands of ions flow through a channel protein for each opening
Kandel 5-19
A transporter (or pump) protein moves a few ions for each conformational change
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Chem 1 textbook (OGC)Figure 12-10
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;ln zFVK
KRTG
o
i at equilibrium 0G ; therefore
o
i
K
K
zF
RTV ln
(we’ll assume that z = +1) An e-fold ratio of K+ concentration ( oi KK )
therefore leads to a potential difference of .F
RT
R = 1.99 cal/mol oK; T = 300o; F = 9.65 x 104 C/mol (C is abbrev for coulomb).
Therefore F
RT = cal/C.106
molC10965.9
300molcal99.1
3
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Now, 1 cal = 4.18 J (J is the abbreviation for joule), and 1 J = 1 V x 1 C.
Therefore F
RT = mV25calCV18.4cal/C106 3 .
Thus an e-fold concentration ratio gives a -25 mV membrane potential.
Deriving the Nernst potential (chemistry units)
OGN Figure 7-7
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Deriving the Nernst potential (physics units)
R = N k , w h e r e N i s A v o g a d r o ’ s n u m b e r a n d k i s B o l t z m a n n ’ s c o n s t a n t ; A n d F = N e , w h e r e e i s t h e c h a r g e o n t h e e l e c t r o n .
T h e r e f o r e mV25106.1
3001038.119
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C
J
e
kT
F
RT
( w e a r e f a m i l i a r w i t h t h e s t a t e m e n t t h a t k T = 2 5 m e V ) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - A n d a 1 0 - f o l d c o n c e n t r a t i o n r a t i o l e a d s t o a m e m b r a n e p o t e n t i a l o f
mV5810ln F
RT
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Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
What is the selective advantage . . .that the membrane is permeable at rest to K+ rather than to Na+?
[K+]I = 140 mM; [Na+]I = 10 mM. A leak of 10 mM: [Na+] would increase from ~ 10 mM to 20 mM, doubling
[Na+]I and causing a 17 mV change in the Nernst potential.
a small inward leak of Na+ would change the internal [Na+] by fractionally more than
a small outward leakage of K+ would change internal [K+ ]
But a similar outward leak in K+ would decrease [K+]i from 140 mM to 130 mM, causing a < 2 mV change in
the Nernst potential for [K+].
Conclusion: cell function is more stable when the resting permeability is to K+ .
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Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
What is the selective advantage . . .that the membrane is permeable at rest to K+ rather than to Na+?
Conclusion: cell function is more stable when the resting permeability is to K+ .
Indeed, there are many dozens of K+ channels in the genome, but only ~ 10 Na+ channels.
K channels are metabolically “free” at rest.
Important, because the “Na/K pump” splits ~ 2/3 of the brain’s ATP.
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Under what circumstances do neurons use Cl- fluxes? Apparently it’s not straightforward to make a permeability pathway that distinguishes among anions using protein side chains. Therefore there is no “anion pair” corresponding to K+ / Na+. Few cells use anions to set the resting potential.
But most postsynaptic inhibitory channels do use anion (mainly Cl-) fluxes.
Could neurons utilize plasma membrane H+ fluxes? Probably not.
There are not enough protons to make a bulk flow, required for robustly
maintaining the ion concentration gradients.
(but some very small organelles (~ 0.1 m) and bacteria do indeed store energy as H+ gradients).
Other monovalent ions
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What is the selective advantage that cells maintain Ca2+ at such low levels?
Cells made a commitment, more than a billion yr ago, to use high-energy
phosphate bonds for energy storage.
Therefore cells contain a high internal phosphate concentration.
But Ca phosphate is insoluble near neutral pH.
Therefore cells cannot have appreciable concentration of Ca2+;
they typically maintain Ca2+ at < 10 –8 M.
What is the selective advantage that cells don’t use Mg2+ fluxes?
The answer derives from considering the atomic-scale structure of a K+ -
selective channel (next slide), which received the 2003 Nobel Chemistry Prize:
http://www.its.caltech.edu/~lester/Bi-150/kcsa.pdb
(A suitable molecular graphics program, such as Swiss-prot viewer, must be installed on your computer)
Divalent Cations
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In the “selectivity filter” of most K+ channels,
K+ ions lose their waters of hydration and are co-ordinated by backbone carbonyl groups
(Like Kandel Figure 5-15)
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Atomic-scale structure of (bacterial) Na+ channels (2011, 2012) shows that here, too, partial loss of water is important for permeation
Views from the
extracellular solution
(As in Kandel Figure 5-1, Na+ channels select with their side chains)
Views from the
membrane plane
The entire water-like pathway Payandeh et al, Nature 2011; Zhang et al, Nature 2012
PDB files
4EKW, 4DXW
Na+ , K+1 ns
(~ 109/s) Na+ , K+, and Ca2+ can flow through single channels at rates > 1000-fold greater than Mg2+
Ca2+5 ns
(2 x 108/s)
Mg2+
10 s
(105/s)As the most charge-dense cation, Mg2+ holds its waters of hydration most tightly.
Time required to exchange waters of hydration
The “surface / volume” principle:
We know of several Mg2 transporters,
but Mg2+ channels apparently exist only in mitochondria & bacteria.
Moomaw & Maguire, Physiologist, 2008 23
Zigmond et al. (Eds.) Fundamental Neuroscience, © Sinauer (1999)
. . . this is crucial for learning and memory
Indeed, Mg2+ remains in the NMDA receptor channel so long . . . that it becomes a voltage-dependent blocker
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Kandel 6-5
Primary (ATP-coupled) vs secondary (ion-coupled) pumps / transporters
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These gradients can be used in two ways:
1. The gradients are used for uphill “exchange” to control the concentrations of other small molecules. 2. Transient, local increases in intracellular Ca2+ and Na+ concentrations can now be used for signaling inside cells!
Next image
Cells have evolved elaborate processes for pumping out intracellular
Na+ and Ca2+
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Ion-coupled transporters in the plasma membrane also control the levels of neurotransmitters
Antidepressants (“SSRIs” = serotonin-selectivereuptake inhibitors):Prozac, Zoloft, Paxil, Celexa, Luvox
Drugs of abuse: MDMA
Attention-deficit disorder medications:
Ritalin, Dexedrine, Adderall,Strattera (?)
Drugs of abuse: cocaine amphetamine
Na+-coupledcell membrane serotonintransporter
Na+-coupledcell membrane dopamine transporter
NH
HO NH3+
HO
HO
H2C
CH2
NH3+
cytosol
outside
Presynapticterminals
Trademarks:
Marks material that won’t appear on an exam
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The “alternating access” mechanism explains both ATP-driven (primary) and ion-coupled (secondary) transport
Based on structure(Ca2+ pump)
Based on biochemistry
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These proteins have evolved in a natural—perhaps necessary--way to provide that
• The resting potential arises via selective permeability to K+
This selective permeability also leads to the Nernst potential. Transient breakdowns in membrane potential are used as nerve signals.
• Neuronal and non-neuronal cells also signal via transient influxes of Na+ and Ca2+.
3 classes of proteins that transport ions across membranes:
modified fromAlberts 4th 11-4
© Garland
Ion channels that flux many ions per event
Ion-coupled transporters
“Active” transporters (pumps) that split ATP
(transporter)
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Transport proteins (transporters, pumps, and channels)
are 5% of the human genome . . .
~ 1250 genes
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Come to class, please. Quizzes occur randomly, During ~ 1/3 of the lectures,
And count for 10% of your grade.
Exams will cover material in the lectures and the required readings in Kandel.
Don’t consult previous problem sets or exams.
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https://www.coursera.org/#course/drugsandbrain
Coursera
Drugs and the Brain
7 weeks of lectures
Partial overlap with Bi/CNS 150.
Extra credit for Bi/CNS 150 students (~ 1/3 grade)..Credit will be assigned **after** we make the Bi/BNS 150 curve;
Therefore you won’t be penalized for not taking the MOOC.
You must complete all MOOC work by 19 December 2013
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If you drop the course,
or if you register late,
please email Teagan
(in addition to the Registrar’s cards).
Also, if you want to change sections,
please email Teagan
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End of Lecture 1
Henry Lester’s office hours occur at an unusual time today: 12:30 -1:15 PM.
At the usual place: Outside the Red Door
