Welcome to the Physiology Course

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Welcome to the Physiology Course Course
Director Myles Akabas Dept. of
Physiology x-3360 Ull-209
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Physiology Course Fall 2008 4 semester hours
Course Director Myles Akabas x-3360
makabas_at_aecom.yu.edu Ull 209 Classroom
Belfer 708 unless indicated otherwise on the
schedule Classtime 1015 AM 1145 If you try
to arrive on time, we will try to finish on
time. Course runs from 9/2/08 through 1/23/09
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• Course Requirements/Recommendations
• Attend lectures
• Readings
• No syllabus we will not spoon feed you we
  expect you to put in the intellectual effort to
  learn the material
• Class handouts required readings
• Textbook none required some on reserve in
  library
• Medical Physiology by Boron and Boulpaep
• Physiology by Berne and Levy
• Textbook of Medical Physiology by Guyton
• Review of Medical Physiology (Lange series) by
  Ganong

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Course Requirements/Recommendations Continued
3) Physiology Course Web Site http//akabaslab.ae
com.yu.edu/ Then go to MSTP Physiology
Course a) Course schedule b) Powerpoint or
pdf files with lecture presentations c) pdf
files for some articles in assigned readings
color figures supplementary
readings Thanks to David Liebelt for setting it
up.
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Course Requirements/Recommendations Continued
4) Participate in class ask questions 5)
Review sessions before exams come with
questions 6) Exams a) four b) open book, learn
concepts, think, dont memorize facts Open Book
does not mean the answers are in the book,
synthesize course material, analyze questions,
write intelligent, well constructed essays c)
your work and yours alone can study together
honor system d) take home, 5 hours maximum,
honor system, if takes longer you did not study
adequately, last exam may be in class e) short
essay format some calculations f) Exam Due
Dates 10/6/08, 11/21/08, 1/5/09, 1/23/09 g)
failure is possible, but not desirable
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Eighth Year This Course is Being Offered

• We need your feedback to improve the course!
• There have been changes since last year.
• new lectures, review sessions, web site
• Comments/criticisms welcome throughout the
  course.
• Lectures that are not clear
• Material not covered
• Better order for material apologies in advance
• Lecture/readings evaluation forms with exams
• Next year need comments as to how well prepared
  you are for
• second year pathophysiology courses and Medical
  Boards

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Physiology is Different Than Histology or Anatomy
Concepts vs Memorization like physics there are
things to memorize but it is the concepts that
are essential you must put in the intellectual
effort to understand the concepts you must think
about the ideas to become comfortable with
them do not expect that you will learn
physiology by cramming for exams Dynamic vs
Static subject new discoveries new
insights so what you learn today may need to be
revised in the future
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What is the difference between Steady State
and Equilibrium?
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Steady State vs Equilibrium The difference
between Life and Death
equilibrium no net change and no dissipation of
energy steady state no net change but
continuous dissipation of energy or matter Life
is a steady state process. We continuously
dissipate energy to keep away from equilibrium.
steady state rate of inflow matches rate of
efflux but flux through the system
equilibrium no net change
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What is Physiology?
Focuses on homeostasis, the maintenance of
important parameters in living organisms in a
narrow range (in the steady state) in the face of
significant environmental fluctuations
Example body temperature
elevated
Core Body Temperature Sensors
normal range
decreased
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Cold Sensitive Ion Channels Transient Receptor
Potential M8 (TRPM8)
Peier et al., (2002) Cell 108707-715
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Molecular Basis of Temperature Sensation
Transient Receptor Potential (TRP) Channels
Dhaka et al. (2006) Annu. Rev. Neurosci.
29135-161
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Components of a Physiological System
EFFECTORS
elevated
INFORMATION INTEGRATION Feedback control system
SENSORS
normal range
decreased
EFFECTORS
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Examples of Homeostatically Regulated Properties
body temperature blood pressure cardiac
output blood composition (ions, sugars,
proteins, etc.) body osmolarity oxygen and
carbon dioxide content of blood acid-base
balance
How does the body measure physiological
parameters? molecular mechanisms cellular
mechanisms
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Example Factors Effecting a Physiological
Parameter
INTEGRATINGCENTERS
SENSORS
metabolic demands
DETERMINANTS
stretch receptors
cardiac output heart rate stroke
volume contractility
FUNCTIONS
Arterial Blood Pressure
tissue perfusion substrate delivery
waste removal
vascular capacity arterial vs venous
elasticity of vascular wall
blood volume distribution arterial vs venous
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Physiology is the Basis of Medicine
many diseases cause organ dysfunction medicine tr
ies to correct dysfunction or minimize its
effects trying to restore system towards
normal homeostatic setpoint need to understand
physiological parameters that can be
manipulated Example Congestive Heart Failure
(CHF) leads to pump failure inability to
maintain adequate level of circulation need to
know causes of failure some may be reversible
others irreversible if irreversible what else
can be done to maximize pumping minimize
symptoms changes in blood volume, arterial or
venous blood pressure at molecular level need to
know potential targets that can be modulated
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Major Clinical Issues Related to the Course

• Cardiac Physiology and heart failure?
• Cardiac electrophysiology and arrthythmias
• Renal physiology and the effects of chronic renal
  disease
• Regulation of blood volume and composition and
  chronic renal failure
• Blood Pressure, circulatory physiology and
  hypertension (HTN)
• Acid-Base balance renal and respiratory diseases

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An Evolutionary View Cellular Physiology vs
Whole Animal Physiology
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Unicellular Ancestor
Intracellular
Cell Membrane
Extracellular
Possibly the decisive step (in the origin of
life) was the formation of the first cell, in
which chain molecules of at least two of three
types now represented by nucleic acids, proteins,
and polysaccharides were enclosed in a
semi-permeable membrane which kept them together
but let food in. J.B.S. Haldane (1954)
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Cell Membrane
two major components lipid bilayer integral
membrane proteins

http//cellbio.utmb.edu/cellbio/membrane_intro.htm
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The Hydrophobic Effect An Important Force in
Lipid Bilayer Formation or Why Oil Does Not Mix
With Water
The antipathy of the paraffin-chain for water
is, however, frequently misunderstood. There
is no question of actual repulsion between
individual water molecules and paraffin chains,
nor is there any very strong attraction of
paraffin chains for one another. There is,
however, a very strong attraction of water
molecules for one another in comparison with
which the paraffin-paraffin or paraffin-water
attractions are very slight.
G.S. Hartley (1936)
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Water Molecules are Polar
dipole moment
?-
?-
?
?
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Water Molecules Can Form 4 Hydrogen Bonds
most other molecules less than 25 Da are
gases at room temperature
weak electrostatic interactions
Comparison Of The Energy In Various Bonds
C - C covalent bond 80 kcal/mol ATP High
Energy Phosphate bond 12 kcal/mol Hydrogen
bond 3-7 kcal/mol van der Waals
interactions 1 kcal/mol
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Phospholipid Molecules Are Amphipathic They Have
Polar And Non-polar Regions
Polar Headgroup
Hydrophobic Fatty Acyl Chains
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Cell Membrane A Traditional View Static and Rigid
two major components lipid bilayer integral
membrane proteins
http//www.sirinet.net/jgjohnso/bilayer.html
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Bilayer is Not as Rigid or Static as it is
Usually Depicted
Importance of thermal motion at the molecular
level
Life is dynamic constant fluctuations
http//www.umass.edu/microbio/rasmol/cutft.gif
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Lipid Bilayer is a Dynamic Structure
Neutron diffraction thermal motion probability
of localization interface region hydrophobic core
http//blanco.biomol.uci.edu/Bilayer_Struc.html
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Requirements for Survival of Unicellular Organism
2) Export wastes

• Import metabolic
• substrates

3) Maintain cell volume 4) Energy generation 5)
Build and degrade proteins, nucleic acids,
etc. 6) Reproduce
Cells evolved to perform these functions in
environment of an infinite ocean of extracellular
fluid
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Cells Evolved to Accomplish Necessary Membrane
Transport
25 35 of ORF inferred to be integral membrane
proteins Polytopic integral membrane proteins
likely to be transporters or channels 10 15
of most genomes
FROM http//www.membranetransport.org/ http//co
mpbiol.plosjournals.org/perlserv/?requestget-docu
mentdoi10.1371/journal.pcbi.0010027 http//www-b
iology.ucsd.edu/msaier/transport/ Paulsen et al.
(1998) Microbial genome analyses global
comparisons of transport capabilities based on
phylogenies, bioenergetics and substrate
specificities. J. Mol. Biol. 277 573-592.
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Evolution of Multicellular Organisms Created a
Fundamental Problem
2 Classes of cells in primitive multicellular
organism
Cells with relatively free access to ocean for
uptake of metabolic substrates and export of
wastes
Cells with limited access to ocean
SOLUTION 1) Create a personal ocean/extracellular
fluid. 2) Circulate the extracellular
fluid so that it comes in
contact all cells. 3) Need to maintain
composition and volume of this fluid.
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Role of Most Organ Systems Relates to
Extracellular Fluid
1) The extracellular fluid (blood) brings
metabolic substrates and removes waste
products. 2) Need to maintain the flow (blood
pressure) and composition of the extracellular
fluid so that it comes into contact with each
cell in the body.
Vascular System conduits to bring extracellular
fluid in contact with each cell Heart pump to
move the fluid through the vascular system Kidney
maintain the composition and volume of the
extracellular fluid Lungs bring oxygen into
blood and eliminate carbon dioxide Intestines
nutrient intake into extracellular fluid Liver
nutrient processing Brain integration of all of
these systems sensors, effectors, communication
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Fluid Volumes in Humans
Total body water 2/3 body weight 1 liter H2O
1 kg Intracellular volume 2/3 total body
water Extracellular volume 1/3 total body
water Interstitial volume 2/3 extracellular
volume 2/9 total body water Plasma
volume 1/3 extracellular volume
1/9 total body water
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Ionic Composition of Body Fluid Volumes
ICV ECV Sea Water Cations Na 5-15 mM 140
mM 475 mM K 140 mM 3-5 mM 10 mM Ca2 10-4
mM 2.5 mM 10 mM Mg2 15 mM 1 mM 54 mM
Anions Cl- 5-20 mM 100 mM 554 mM HCO3- 15
mM 25 mM 2 mM Phosphates 50 meq/l 2
meq/l trace Proteins 50 meq/l 15
meq/l absent 30 g/dl 7 g/dl Intracellular
phosphates are complex organic phosphates, DNA,
RNA, nucleotides, etc. Extracellular
phosphates are mainly inorganic
phosphate. Protein in the ECV is largely
confined to the Plasma space, the protein
concentration in the Interstitial space is 1 g/dl
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Chemical Gradients are a form of Potential Energy
K
Na
K
Na
energy is stored in transmembrane ion
gradients takes energy to create gradients
and, if there is a leak, it takes energy to
maintain the gradients Energy in ion gradients
can be captured by transport proteins Example -
mitochondria
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Mitochondria and Chloroplasts Chemi-Osmotic
Hypothesis Proton Gradient is an Intermediate in
the ATP Synthesis Process
H
H
ATP Synthase F1F0-ATPase
Electron Transport Chain
ADP P
ATP
CHO O2
H
H
CO2 H2O
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Overview of Course
Membrane Physiology transport processes electric
al activity synaptic transmission membrane
receptors and second messengers Epithelial
Physiology Muscle Physiology Skeletal, Smooth ,
Cardiac Circulatory Physiology Cardiac Physiology
pump function Renal Physiology Water and
Regulation of Body Osmolarity Blood Pressure and
Volume Regulation Pulmonary Physiology
Acid-Base Balance
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What is Physiology?
Focuses on homeostasis, the maintenance of
important parameters in living organisms in a
narrow range (in the steady state) in the face of
significant environmental fluctuations
Example body temperature
elevated
Core Body Temperature Sensors
normal range
decreased