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Water Channels 2003 Chemistry Nobel Prize. Kristi McKee SFASU Fall 2003 Scientific Discovery. Importance of this Award. 70% of living systems are made up of water. Have to have some type of mechanism to move water and important ions around. Cell Membrane.

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water channels 2003 chemistry nobel prize

Water Channels2003 Chemistry Nobel Prize

Kristi McKee

SFASU Fall 2003

Scientific Discovery

importance of this award
Importance of this Award
  • 70% of living systems are made up of water.
  • Have to have some type of mechanism to move water and important ions around.
cell membrane
Cell Membrane
  • The cell membrane is important in protecting the cells organelles from the environment and transporting nutrients in and waste out of the cell.
cell membrane1
Cell Membrane
  • The cell membrane is made up of mostly phospholipidis and proteins.
cell membrane2
Cell Membrane
  • Phospholipids have a hydrophilic and hydrophobic ends.
  • The phosphate head is charged while the carbon tail is not charged.
cell membrane3
Cell Membrane
  • Three types of predominant proteins in the membrane:
    • Transport Proteins
    • Marker Proteins
    • Receptor Proteins
cell membrane4
Cell Membrane
  • Transport Proteins – regulate transport and diffusion across membrane. There are two forms:
    • Carrier
    • Channel
carrier proteins
Carrier Proteins
  • They do not extend the whole distance of membrane, instead move back and forth carrying nutrients and waste in and out.
channel proteins
Channel Proteins
  • Some act as a passive pore to allow diffusion of water and some other molecules.
  • Does not require energy.
history
History
  • 1890 Wilhelm Ostwald proposed the idea that electric signals were produced by ions moving in and out of the cell. He was awarded the Nobel Prize in 1909 for the discovery.
history1
History
  • John Eccles, Alan Hodgkin and Andrew Huxley were able to show how potassium and sodium ions were involved in chemical cascades (i.e. eyes watering, muscles contracting) They were awarded a Nobel Prize in the 1963.
history2
HIstory
  • Jens Skou awarded the Nobel Prize in Chemistry in 1997 for discovery of Sodium-Potassium Pumps.
history3
History
  • In the 1970’s scientists were able to prove that some channels were specific to only particular type of ions.
  • However, no one had yet been able to see what a water channel actually does, how it looks.
advance of science
Advance of Science
  • In the late 1980’s protein science had advanced for the study of molecular machinery of how proteins may work and function.
  • By 1992 scientists were able to identify which proteins were involved in channels.
peter agre
Peter Agre
  • BA in Chemistry 1970 Augsburg College
  • MD 1974 from Johns Hopkins University School of Medicine
  • 1974 – 75 Postdoctoral Fellowship Johns Hopkins Dept of Pharamacology
slide18
Agre
  • 1975 – 78 Internship and Residency at Case Western Reserve University Dept. of Medicine
  • 1978 – 80 Postdoctoral Fellowship At Univ. of N. Carolina at Chapel Hill Dept. of Medicine Hematology/Oncology Div.
  • 1980 – 81 Clinical Asst. Professor of Medicine Univ. of N. Carolina at Chapel Hill
slide19
Agre
  • 1980 – 81 Senior Clinical Research Scientist
  • 1981 – 83 Research Associate Johns Hopkins School of Medicine Dept. of Cell Biology/Anatomy and Medicine
  • 1984 – 93 Asst. Professor Johns Hopkins
  • 1990 – 94 Co-Director Office of Research Planning Dept. of Medicine
slide20
Agre
  • 1993 – present Professor Johns Hopkins School of Medicine Departments of Biological Chemistry and Medicine
  • 1996 – 1999 Director of John Hopkins Graduate Program in Cellular and Molecular Medicine (CMM)
  • 1999 – present Chair Advisory Board Johns Hopkins Graduate Program in CCM
agre s work
Agre’s Work
  • In mid-1980’s he studied various proteins found in the membrane of red blood cells and also found one in the kidneys and was able to determine the peptide sequence and the corresponding DNA sequence. (CHIP28 28kDa)
agre s work1
Agre’s Work
  • Expressed the CHIP28 in Xenopus oocytes and placed in hypo-osmotic medium and noticed the cells swelling rapidly.
agre s work2
Agre’s Work
  • He tested his theory by a simple experiment by comparing two cells one with this protein and one without. When exposed to water the ones with the protein swelled and one without remain unchanged.
agre s work4
Agre’s Work
  • Also ran trials on artificial cells called liposome (type of soap bubble with water on inside and out) Also found the cells with the protein (CHIP28) inserted in membrane acted as previous cells.
  • He termed these channel proteins aquaporin, “water pore”.
agre s work5
Agre’s Work
  • From knowledge that Hg+2 blocks water movement in cells he was able to show the cells with the protein were also rendered inactive by the mercury ions. This finding made him believe that his discovery was actually a water channel.
agre s work6
Agre’s Work
  • In 2000 with other research scientists, he was able to show the first three-dimensional of an aquaporin (Aquaporin-1 from human red blood cell).
the other half
The Other Half

Roderick MacKinnon

roderick mackinnon
Roderick MacKinnon
  • BS 1978 Brandeis University in Biochemistry
  • MD 1982 Tufts Medical School in Boston
  • 1985 Completed residency at Beth Israel Hospital, Harvard, board Certified in internal medicine.
mackinnon
MacKinnon
  • 1985 – 86 Postdoctoral Fellowship in Dept of Medicine at Beth Israel Hospital.
  • 1986 – 89 Postdoctoral Fellowship in Dept. of Biochemistry at Brandeis.
  • 1989 – 91 Asst Professor in Dept. of Cellular and Molecular Physiology, Harvard Medical School.
mackinnon1
MacKinnon
  • 1991 – 92 Asst. Professor in Dept. of Neurobiology, Harvard Medical School.
  • 1992 received PEW Scholar in Biomedical Sciences and McKnight Scholars Award
  • 1995 Received Biophysical Society Young Investigator Award and was promoted to full Professor at Harvard Medical School Dept. of Neurobiology.
mackinnon2
MacKinnon
  • 1996 – Present Professor in Laboratory of Molecular Neurobiology and Biophysics and Rockefeller University, New York City. Also an Investigator at the Howard Hughes Medical Institute.
  • 1999 Awarded Lasker Award for Basic Medical Research on work with ion channels.
mackinnon3
MacKinnon
  • Took a new approach to try and crack the controversy of ion channel proteins.
  • First worked with scorpion toxin that was discovered to block potassium channels that lead to the discovery of the shaker gene.
mackinnon4
MacKinnon
  • Discovered that potassium channels had to be tetramers by binomial statistics and the toxin experiments.
mackinnon5
MacKinnon
  • Using his skills and the advancements of X-ray crystallography, MacKinnon taught himself the fundamentals and presented the structure of an ion channel in April of 1998 (KcsA from the bacterium Streptomyces lividans).
  • Also revealed how ion channel functions at an atomic level.
mackinnon7
MacKinnon
  • Two types of ion channels studied and discovered how they differentiated between ions:
    • Potassium channels
    • Sodium channels
mackinnon8
MacKinnon
  • The channels had a selective “filter” in the P-loop, and a sensor to determine when to let the ions in and out of the cell.
  • Discovered in the potassium channel that the spacing between the K+ and the oxygen atoms in the filter and the sodium ions do not fit so they remain behind in the water solution.
mackinnon10
MacKinnon
  • Ion Channel GatingIon channel gating refers to opening and closing of the ion conduction pore in response to a specific stimulus.
  • Certain channels open when ligands bind (ligand-gated channels); others open in response to membrane voltage (voltage-gated channels).
mackinnon11
MacKinnon
  • Studied diffusion-limited rates by analysis of ion conduction on potassium channels using K+ and Rb+
  • Used Rb because they are know to penetrate K channels.
  • Found K+ ion is passed and rehydrated in approximently ten nanoseconds.
channels
Channels
  • Types of channels
    • Water – They are responsible to transportation of water in and out of the cell.
    • Ion – Move ions in and out to conduct such things as signal cascades.
    • Aquaglyceroporins – Trasport glycerol and other small molecules across membrane.
channels1
Channels
  • There are now 11 different variants of these channels in the human body and more may still be discovered.
  • They are responsible for many reactions in the body one major function is done in the kidneys.
body functions
Body Functions
  • 170 liters of primary urine produced in 24 hours but only approximently 1 liter is excreted per day.
  • This is due to the mechanisms in kidneys:
    • 70% of water reabsorbed by AQP1 into blood
    • 10% of water reabsorbed by AQP2
diseases related to ion channels
Diseases related to Ion Channels
  • Several disease states are related to dysfunctional ion channels.
    • cardiac arrhythmias
    • diabetes
    • hypertension
    • angina pectoris
    • epilepsy
diseases related to defects with ion channels
Diseases Related to Defects with Ion Channels
  • Alzheimer’s Disease
  • Parkinson’s
  • Schizophrenia
  • Thought to result from dysfunction of voltage gated channels
defects in ion channels
Defects in Ion Channels
  • 1989 cystic fibrosis was first discovered to be as a defect in ion channels.
  • Epilepsy caused from synchronised bursts in nerve cells in the brain that result in seizures. Disorder was found in the beta subunit or in the alpha subunit in voltage-gated sodium channel. Defect in a single change of amio acid residue.
defect in aquaporins
Defect in Aquaporins
  • A deficiency in the antidiureti hormone, vasopressin, may be affected by diabetes insipidus and show an increase of urine excretion to 10 – 15 liters a day.
drug targeting
Drug Targeting
  • Already today, drugs targeting ion channels generates over 6 billion dollars in sales per annum. According to the FDA, the number of new approved drugs targeting ion channels is equal to or even higher than that for drugs targeting proteases, polymerases and reverse transcriptases.
resources
Resources
  • Agre, Peter; Bonhivers, Melanie; Borgnia, Mario J. “The Aquaporins, Blueprints for Cellular Plumbing Systems,” Jounal of Biological Chemistry Vol. 273, Issue 24. June 12, 1998. pp 14659 – 14662.
  • “An Interview with Roderick MacKinnon,” Lasker Foundation. www.laskerfoundation.org/awards/library/1999b_int_mr2.shtml.
  • “Boigraphy of Roderick MacKinnon” Lasker Foundation. www.laskerfoundation.org/awards/library/ 1999b_boi_mr.shtml
  • Bowen, R. “Aquaporins: Water Channels” www.arbl.cvmbs.colostate.edu/hbooks/molecules/aquaporins.html
resources1
Resources
  • Cell Membrane Cartoon. www.people.virginia.edu/~rjh9u/cellmembrane.html
  • “Chemistry Channels” Spotlight www.psigate.ac.uk/spotlight/issue13b/chemistry.html
  • Dworakowska, Beata; Dolowy, Krzysztof. “Ion Channels-related Diseases,” Acta Biochimica Polonica Vol. 47 No. 3, July 27, 2000. pp. 685 – 703.
  • Hard, Trude. “Potassium Channels in Guard Cells – From Phenomenon to Structural Analysis,” www.iwf.de/iwfeng/3medien/33db/333/c7041.html
resources2
Resources
  • Jensen, Morten O; Tajkhorshid, Emad; Schulten, Klaus. “Electrostatic Tuning of Permeation and Selectivity in Aquaporin Water Channels,” Boiphysical Journal. Vol 85. November 2003. pp 2884 – 2899.
  • Karow, Julia. “Interview with Roderick MacKinnon,” March 4, 2002. Scientific American. www.sciam.com
  • Keeley, Jim. “Researchers Discover Structure of Nature’s ‘Circuit Breaker,’” April 30, 2003. www.eurekalert.org/pub_releases/2003-04/hhmi-rds042903.php
resources3
Resources
  • Morals-Cabral, Joao H; Zhou; Yufeng; MacKinnon, Roderick. “Energetic Optimization of Ion Conduction Rate by the K+ Selectivity Filter,” Nature. Vol. 414, November 2001pp. 37 – 42.
  • Morrill, James A.; MacKinnon, Roderick. “Isolation of a Single Carboxyl-Carboxylate Proton Binding Site in the Pore of a Cyclic Nucleotide-gated Channel,” Journal of General Physiology. Vol. 114 July 1999. pp. 71 – 83.
resources4
Resources
  • Nobel Prize in Chemistry. Advanced Information for Public. www.nobel.se
  • “Nobel Prize in Chemistry 2003 - Information for the Public” www.nobel.se/chemistry/laureates/2003/public.html
  • Phospholipid Structure. www.bact.wisc.edu/microtextbook/bacterialstructure/membraneGen.html
  • “Structure and Mechanism of Ion Channels,” www.hhmi.org/research/investigators/mackinnon.html
resources5
Resources
  • “Shaping better Understanding of Potassium Channels,” www.hhmi.org/news/mackinnon6.html
  • Structural Studies Reveal How Potassium Channels are Inactivated,” www.hhmi.org/newsmackinnon4.html
  • The Virtual Cell Web Page Ch 3 Cell Biology. www.personal.tmlp.com/Jimr57/textbook/chapter3.htm
  • Voltage Dependent Potassium Channel. Roderick MacKinnon, Ion Channels. www.osti.gov/accomplishments/mackinnon.html