A Sense of Smell: Olfactory Receptors

 
The sense of smell in vertebrates is mediated by proteins called olfactory receptors (OR). In the case of mammals, these proteins are embedded in the membranes of sensory neurons in the nasal cavity. Each neuron is thought to contain a single type of olfactory receptor responding to a single type of odorant.

When an odorant binds to the outside of the olfactory receptor it transmits a signal to the interior of the cell. This signal triggers a response that excites the neuron and causes it to pass a message back along the axon to the brain. The brain then interprets the excitation as a specifc odor.

Olfactory receptors belong to a class of proteins called G-protein coupled receptors (GPCR). These proteins possess a characteristic bundle of seven membrane-spanning α-helices forming a tube within the membrane. The binding site for the specific odorant is located within the tube.

It has not been possible to crystallize any of the GPCR's that have been identified but the structures of some similar proteins are known. This enables workers to predict the structure of olfactory receptors using computer models. The models are then tested in various ways to confirm the predictions. We have a pretty good idea of what the olfactory receptors look like.

An example is shown in the figure on the left from a paper by Hall et al. (2004). This is the predicted structure of a mouse olfactory receptor that binds octanol. (Octanol is a sweet-smelling alcohol.) The bound molecule is shown as a red stick model in the side view (left) and the top view (right). The outside of the cell is at the top and that's where the odorant penetrates to the binding site.

The seven coils that you see in the structure are the seven α-helices that span the membrane. When the odorant binds, it changes the structure of the protein a little bit and this slight change includes the part of the receptor at the bottom, which is inside the cell. The change is enough to affect the binding of another protein, called a G-protein. This is what triggers the response.

Many different kinds of receptors activate a signalling pathway in the same manner as the olfactory receptors. A typical example is shown in the diagram below. In this case the signal is triggered by a hormone, but the same principle applies to signals triggered by odorants.


Look at the stimulatory pathway on the left. This is how the olfactory receptors work. When an odorant binds, the conformational change is transmitted through the receptor (R_s) to the inside surface of the membrane. G-protein (green) normally binds to the bottom surface of the receptor but when the receptor is triggered, G-protein is released and moves over to bind to another membrane protein called adenylate cyclase. The release and movement of G-protein is coupled to exchange of GDP for GTP. (GTP is a nucleotide like ATP. The proteins are called G-proteins because they bind GDP/GTP.)

Adenlyate cyclase is an enzyme that catalyzes the conversion of ATP to cyclic AMP (cAMP). cAMP in turn activates an enzyme called protein kinase A. Kinases are enzymes that attach phosphate groups to proteins. In this case, protein kinase A phosphorylates a protein within the neurons converting it from an inactive to an active form. Eventually the signal is transmitted to membrane pumps that are stimulated to alter the flow of charged ions into and out of the cell. This results in an action potential that passes up the axon to the brain.

This is a classic signal transduction pathway. The example shown in the figure is a simplified version with only a single protein kinase phosphorylation. In most cases there is a cascade of phosphorylations (and dephosphrylations) involving a number of different proteins. The study of signal transduction cascades is a major focus of hundreds of biochemistry labs.

The net result of all this biochemistry is that the presence of an odorant in your nose will eventually cause your brain to recognize it, as long as you have a receptor for that odorant. We have 388 different olfactory receptors so we can detect lots of different smells, including cat urine. Mice have 1037 different olfactory receptors so they can probably smell things that we can't. Maybe they can smell cats directly.

The olfactory receptor genes were discovered by Linda Buck and Richard Axel in 1991. They got the Nobel Prize in 2004 (see tomorrow's "Nobel Laureates").

The evolution of these genes in vertebrates raises some interesting questions about mechanisms of evolution. We'll learn about birth-and-death evolution later on this week.

Hall, S., Floriano, W.B., Vaidehi, N. and Goddard III, W.A. (2004) Predicted 3-D Structure for Mouse 17 and Rat 17 Olfactory Receptors and Comparison of Predicted Odor Recognition Profiles with Experiment. Chem. Senses 28: 595-616.

Theme: Nobel Laureates

 
NOBEL LAUREATES

November 13, 2006
Physiology or Medicine 1922
Otto Fritz Meyerhof
"for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle"

November 22, 2006
Physiology or Medicine 1964
Jacques Monod
"for their discoveries concerning genetic control of enzyme and virus synthesis"

November 29, 2006
Chemistry 1964
Dorothy Crowfoot Hodgkin
"for her determinations by X-ray techniques of the structures of important biochemical substances"

December 6, 2006
Chemistry 1930
Hans Fischer
"for his researches into the constitution of haemin and chlorophyll and especially for his synthesis of haemin"

December 13, 2006
Chemistry 1902
Hermann Emil Fischer
"in recognition of the extraordinary services he has rendered by his work on sugar and purine syntheses"

December 20, 2006
Physiology or Medicine 1953
Hans Adolf Krebs
"for his discovery of the citric acid cycle"

January 3, 2007
Physiology or Medicine 1982
Sune K. Bergström, Bengt I. Samuelsson, and John R. Vane
"for their discoveries concerning prostaglandins and related biologically active substances"

January 10, 2007
Physiology or Medicine 2004
Richard Axel and Linda B. Buck
"for their discoveries of odorant receptors and the organization of the olfactory system"

Theme

A Sense of Smell
Nobel Laureates: Richard Axel, Linda Buck
January 17, 2007
Physiology or Medicine 1998
Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad
"for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system"

January 24, 2007
Chemistry 1978
Peter D. Mitchell
"for his contribution to the understanding of biological energy transfer through the formulation of the chemiosmotic theory"


January 31, 2007
Chemistry 1988
Johann Deisenhofer, Robert Huber, and Hartmut Michel
"for the determination of the three-dimensional structure of a photosynthetic reaction centre"

February 7, 2007
Physiology or Medicine 1978
Werner Arber, Daniel Nathans, and Hamilton O. Smith
"for the discovery of restriction enzymes and their application to problems of molecular genetics"

February 14, 2007
Chemistry 1972
Christian B. Anfinsen
"for his work on ribonuclease, especially concerning the connection between the amino acid sequence and the biologically active conformation"

February 21, 2007
Physiology or Medicine 1930
Karl Landsteiner
"for his discovery of human blood groups"

February 28, 2007
Chemistry 1937
Walter Norman Haworth
"for his investigations on carbohydrates and vitamin C"

March 7, 2007
Physiology or Medicine 1948
Paul Hermann Müller
"for his discovery of the high efficiency of DDT as a contact poison against several arthropods"

March 14, 2007
Chemistry 1980
Paul Berg
"for his fundamental studies of the biochemistry of nucleic acids, with particular regard to recombinant-DNA"

Theme

Transcription
Nobel Laureate: Roger Kornberg
March 21, 2007
Chemistry 2006
Roger D. Kornberg
"for his studies of the molecular basis of eukaryotic transcription"

March 28, 2007
Physiology or Medicine 1943
Henrik Carl Peter Dam
"for his discovery of vitamin K"
Edward Adelbert Doisy "for his discovery of the chemical nature of vitamin K"

Theme

Blood Clotting
Nobel Laureates: Henrik Dam, Edward Doisy
April 4, 2007
Chemistry 1948
Arne Wilhelm Kaurin Tiselius
"for his research on electrophoresis and adsorption analysis, especially for his discoveries concerning the complex nature of the serum proteins"





April 11, 2007
Physiology or Medicine 1953
Fritz Albert Lipmann
"for his discovery of co-enzyme A and its importance for intermediary metabolism"

Theme

Pyruvate Dehydrogenase
Nobel Laureate: Aaron Klug
April 18, 2007
Chemistry 1982
Aaron Klug
"for his development of crystallographic electron microscopy and his structural elucidation of biologically important nucleic acid-protein complexes"

April 25, 2007
Chemistry 1920
Walther Hermann Nernst
"in recognition of his work in thermochemistry"

May 2, 2007
Physiology or Medicine 1929
Christiaan Eijkman
"for his discovery of the antineuritic vitamin"


May 9, 2007
Physiology or Medicine 1947
Carl Ferdinand Cori and Gerty Theresa Cori, née Radnitz
"for their discovery of the course of the catalytic conversion of glycogen"

May 16, 2007
Chemistry 1907
Eduard Buchner
"for his biochemical researches and his discovery of cell-free fermentation"
[cell free synthesis of alcohol in yeast extracts: vitalism]

May 23, 2007
Physiology or Medicine 1994
Alfred G. Gilman and Martin Rodbell
"for their discovery of G-proteins and the role of these proteins in signal transduction in cells"


May 30, 2007
Physiology or Medicine 1968
Robert W. Holley, Har Gobind Khorana, and Marshall W. Nirenberg
"for their interpretation of the genetic code and its function in protein synthesis"

June 6, 2007
Chemistry 2004
Aaron Ciechanover, Avram Hershko, and Irwin Rose
"for the discovery of ubiquitin-mediated protein degradation"

June 13, 2007
Physiology or Medicine 1945
Sir Alexander Fleming, Ernst Boris Chain, Sir Howard Walter Florey
"for the discovery of penicillin and its curative effect in various infectious diseases"

June 20, 2007
Physiology or Medicine 1993
Richard J. Roberts and Phillip A. Sharp
"for their discoveries of split genes"

June 27, 2007
Physiology or Medicine 1937
Albert von Szent-Györgyi Nagyrapolt
"for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid"

July 4, 2007
Chemistry 1928
Adolf Otto Reinhold Windaus
"for the services rendered through his research into the constitution of the sterols and their connection with the vitamins"

July 11, 2007
Chemistry 1961
Melvin Calvin
"for his research on the carbon dioxide assimilation in plants"

THEME

Deoxyribonucleic Acid (DNA)
Nobel Laureates: Crick, Watson, Wilkins
July 18, 2007
Physiology or Medicine 1962
Francis Harry Compton Crick, James Dewey Watson and Maurice Hugh Frederick Wilkins
"for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material"




July 25, 2007
Physiology or Medicine 1902
Ronald Ross
"for his work on malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it"

and

Physiology or Medicine 1907
Charles Louis Alphonse Laveran
"in recognition of his work on the role played by protozoa in causing diseases"

August 1, 2007
Chemistry 1962
Max Ferdinand Perutz and John Cowdery Kendrew
"for their studies of the structures of globular proteins"

August 8, 2007
Chemistry 1903
Svante August Arrhenius
"in recognition of the extraordinary services he has rendered to the advancement of chemistry by his electrolytic theory of dissociation"

August 22, 2007
Physiology or Medicine 1971
Earl W. Sutherland, Jr.
"for his discoveries concerning the mechanisms of the action of hormones"

August 29, 2007
Chemistry 1937
Paul Karrer
"for his investigations on carotenoids, flavins and vitamins A and B2"

September 5, 2007
Chemistry 1938
Richard Kuhn
"for his work on carotenoids and vitamins"

September 12, 2007
Physiology or Medicine 1969
Max Delbrück, Alfred D. Hershey, and Salvador E. Luria
"for their discoveries concerning the replication mechanism and the genetic structure of viruses"

September 19, 2007
Physiology or Medicine 1933
Thomas Hunt Morgan
"for his discoveries concerning the role played by the chromosome in heredity"

September 26, 2007
Physiology or Medicine 1999
Günter Blobel
"for the discovery that proteins have intrinsic signals that govern their transport and localization in the cell"


October 3, 2007
Physiology or Medicine 1983
Barbara McClintock
"for her discovery of mobile genetic elements"

October 10,2007
Chemistry 1909
Wilhelm Ostwald
"in recognition of his work on catalysis and for his investigations into the fundamental principles governing chemical equilibria and rates of reaction"

October 17, 2007
Chemistry 1926
The (Theodor) Svedberg
"for his work on disperse systems"

October 24, 2007
Chemistry 1946
James Batcheller Sumner
"for his discovery that enzymes can be crystallized"
[crystallization of urease from jack bean]

October 31, 2007
Physiology or Medicine 1959
Arthur Kornberg
"for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid"

November 7, 2007
Physiology or Medicine 1909
Emil Theodor Kocher
"for his work on the physiology, pathology and surgery of the thyroid gland"

November 14, 2007
Chemistry 1975
John Warcup Cornforth
"for his work on the stereochemistry of enzyme-catalyzed reactions"

November 21, 2007
Physiology or Medicine 1964
Konrad Bloch and Feodor Lynen
"for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism"

November 28, 2007
Physiology or Medicine 1992
Edmond Fischer and Edwin Krebs
"for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism"

December 5, 2007
Physiology or Medicine 1955
Hugo Theorell
"for his discoveries concerning the nature and mode of action of oxidation enzymes"

December 12, 2007
Chemistry 1947
Sir Robert Robinson
"for his investigations on plant products of biological importance, especially the alkaloids"

December 19, 2007
Chemistry 1997
Paul Boyer and John Walker
"for their elucidation of the enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP)"

January 9, 2008
Chemistry 1915
Richard Willstätter
"for his researches on plant pigments, especially chlorophyll"

January 16, 2008
Chemistry 1989
Sidney Altman
"for their discovery of catalytic properties of RNA"

January 23, 2008
Chemistry 1989
Thomas R. Cech
"for their discovery of catalytic properties of RNA"

January 30, 2008
Chemistry 1984
Bruce Merrifield
"for his development of methodology for chemical synthesis on a solid matrix"

February 6, 2008
Physiology or Medicine 1965
"for their discoveries concerning genetic control of enzyme and virus synthesis"
François Jacob

February 13, 2008
Physiology or Medicine 1965
"for their discoveries concerning genetic control of enzyme and virus synthesis"
André Lwoff

March 5, 2008
Chemistry 1954
"for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances"
Linus Pauling

March 12, 2008
Physics 1915
"for their services in the analysis of crystal structure by means of X-rays"
Sir William Henry Bragg and Lawrence Bragg

March 19, 2008
Chemistry 1974
"for his fundamental achievements, both theoretical and experimental, in the physical chemistry of the macromolecules"
Paul Flory

April 2, 2008
Chemistry 1918
"for the synthesis of ammonia from its elements"
Fritz Haber

April 9, 2008
Chemistry 2003
"for structural and mechanistic studies of ion channels"
Roderick MacKinnon

April 23, 2008
Chemistry 1957
"for his work on nucleotides and nucleotide co-enzymes"
Lord Alexander Todd

April 30, 2008
Physiology or Medicine 1947
"for his discovery of the part played by the hormone of the anterior pituitary lobe in the metabolism of sugar"
Bernardo Houssay

May 7, 2008
Physiology or Medicine 2000
"for their discoveries concerning signal transduction in the nervous system"
Arvid Carlsson and Paul Greengard

May 14, 2008
Physiology or Medicine 1958
"for their discovery that genes act by regulating definite chemical events"
George Beadle and Edward Tatum

May 21, 2008
Chemistry 1970
"for his discovery of sugar nucleotides and their role in the biosynthesis of carbohydrates"
Luis Leloir

May 28, 2008
"for their preparation of enzymes and virus proteins in a pure form"
Wendell Stanley

June 4, 2008
Physiology or Medicine 1950
"for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects"
Edward Kendall, Tadeus Reichstein and Philip Hench

June 11, 2008
Chemistry 1872
"for their contribution to the understanding of the connection between chemical structure and catalytic activity of the active centre of the ribonuclease molecule"
Stanford Moore and William Stein

June 18, 2008
Physiology or Medicine 1972
"for their discoveries concerning the chemical structure of antibodies"
Gerald M. Edelman and Rodney R. Porter

June 25, 2008
Physiology or Medicine 1987
"for his discovery of the genetic principle for generation of antibody diversity"
Susumu Tonegawa

July 2, 2008
Physiology or Medicine 1929
"for his discovery of the growth-stimulating vitamins"
Sir Frederick Gowland Hopkins

July 9, 2008
Chemistry 2003
"for the discovery of water channels"
Peter Agre

July 16, 2008
Physiology or Medicine 1974
"for their discoveries concerning the structural and functional organization of the cell"
George E. Palade

July 23, 2008
Chemistry 1943
"for his work on the use of isotopes as tracers in the study of chemical processes"
George de Hevesy

July 30, 2008
Physiology or Medicine 1958
"for his discoveries concerning genetic recombination and the organization of the genetic material of bacteria"
Joshua Lederberg

August 6, 2008
Physiology or Medicine 1973
"for their discoveries concerning organization and elicitation of individual and social behaviour patterns"
Karl von Frisch, Konrad Lorenz, Nikolaas Tinbergen

August 13, 2008
Physiology or Medicine 1922
"for his discovery relating to the production of heat in the muscle"
Archibald Hill

August 24, 2008
Physiology or Medicine 1977
"for the development of radioimmunoassays of peptide hormones"
Rosalyn Yalow

August 27, 2008
Chemistry 1929
"for their investigations on the fermentation of sugar and fermentative enzymes"
Arthur Harden

September 3, 2008
Chemistry 1929
"for their investigations on the fermentation of sugar and fermentative enzymes"
Hans Karl August Simon von Euler-Chelpin

September 10, 2008
Chemistry 2002
"for his development of nuclear magnetic resonance spectroscopy for determining the three-dimensional structure of biological macromolecules in solution"
Kurt Wüthrich

September 17, 2008
Physiology or Medicine 1931
"for his discovery of the nature and mode of action of the respiratory enzyme"
Otto Heinrich Warburg

September 25, 2008
Physiology or Medicine 2002
"for their discoveries concerning 'genetic regulation of organ development and programmed cell death'"
Sydney Brenner, H. Robert Horvitz, and John E. Sulston

October 1, 2008
Physiology or Medicine 1959
"for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid"
Severo Ochoa

October 8, 2008
"for his discovery of Prions - a new biological principle of infection"
Stanley Prusiner

October 16, 2008
"for their discoveries concerning the genetic control of early embryonic development"
Christiane Nüsslein-Volhard and Eric F. Wieschaus

October 21, 2008
"for the discovery of the production of mutations by means of X-ray irradiation"
Hermann Joseph Muller

October 29, 2008
"in recognition of the contributions to our knowledge of cell chemistry made through his work on proteins, including the nucleic substances"
Albrecht Kossel

November 5, 2008
"for their preparation of enzymes and virus proteins in a pure form"
John Howard Northrop

November 13, 2008
Physiology or Medicine 1995
"for their discoveries concerning the genetic control of early embryonic development"
Edward Lewis

November 19, 2008
Literature 1930
"for his vigorous and graphic art of description and his ability to create, with wit and humour, new types of characters"
Sinclair Lewis

November 27, 2008
Physiology or Medicine 1988
"for their discoveries of important principles for drug treatment"
George Hitchings and Gertrude Elion

December 3, 2008
Physiology or Medicine 2000
"for their discoveries concerning signal transduction in the nervous system"
Eric Kandel


December 10, 2008
Chemistry 1980
"for their contributions concerning the determination of base sequences in nucleic acids"
Walter Gilbert


December 17, 2008
Chemistry 1980
"for their contributions concerning the determination of base sequences in nucleic acids"
Fred Sanger


December 17, 2008
Chemistry 1990
"for his development of the theory and methodology of organic synthesis"
Elias Corey


January 14, 2009
Physiology and Medicince 1936
"for their discoveries relating to chemical transmission of nerve impulses"
Sir Henry Hallett Dale and Otto Loewi


January 21, 2009
Physiology or Medicince 1936
"for their discoveries concerning the humoral transmittors in the nerve terminals and the mechanism for their storage, release and inactivation"
Ulf von Euler and Julius Axelrod


January 29, 2009
Chemistry 2008
"for the discovery and development of the green fluorescent protein, GFP"
Osamu Shimomura


February 5, 2009
Chemistry 2002
"for their development of soft desorption ionisation methods for mass spectrometric analyses of biological macromolecules"
John B. Fenn and Koichi Tanaka


February 11, 2009
Physiology or Medicine 1974
"for their discoveries concerning the structural and functional organization of the cell"
Christian de Duve


February 20, 2009
Chemistry 1993
"for contributions to the developments of methods within DNA-based chemistry: for his fundamental contributions to the establishment of oligonucleotide-based, site-directed mutagenesis and its development for protein studies"
Michael Smith


February 26, 2009
Chemistry 1993
"for contributions to the developments of methods within DNA-based chemistry: for his fundamental contributions to the establishment of oligonucleotide-based, site-directed mutagenesis and its development for protein studies"
Kary Mullis


March 4, 2009
Physiology or Medicine 1923
"for the discovery of insulin"
Frederick Banting and J.J.R. Macleod


March 11, 2009
Chemistry 1958
"for his work on the structure of proteins, especially that of insulin"
Fred Sanger


March 19, 2009
Chemistry 1960
"for his method to use carbon-14 for age determination in archaeology, geology, geophysics, and other branches of science"
Willard Libby

March 25, 2009
Physiology or Medicine 1952
"for his discovery of streptomycin, the first antibiotic effective against tuberculosis"
Selman Waksman

April 1, 2009
Nobel Prize in Chemistry 1905
"in recognition of his services in the advancement of organic chemistry and the chemical industry, through his work on organic dyes and hydroaromatic compounds"
Adolf von Baeyer

April 8, 2009
Nobel Prize in Physiology or Medicine 2007
"for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells"
Mario Capecchi, Martin Evans, and Oliver Smithies


April 16, 2009
Physiology or Medicine 1951
"for his discoveries concerning yellow fever and how to combat it"
Max Theiler


April 23, 2009
Physiology or Medicine 2001
"for their discoveries of key regulators of the cell cycle"
Sir Paul Nurse

May 1, 2009
Physiology or Medicine 1908
"in recognition of their work on immunity"
Paul Ehrlich

---

How Viagra Works

 
Mondays Molecule was sildenofil (5-[2-ethoxy-5- (4-methylpiperazin-1- ylsulfonyl) phenyl]-1- methyl-3-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one) better known as its citrate salt, Viagra®.

Viagra® is most often used in the treatment of erectile disfunction. The way it works is to inhibit a specific enzyme called phosphodiesterase-5 located in the smooth muscle of the arteries that supply blood to the penis. In order to understand the significnace of this inhibition, we need a little background.

Nitric oxide (NO) is a chemical produced by special nerve cells called NANC nerve cells. (NANC stands for nonadrenergic-noncholinergic.) Under certain, rather special, conditions the brain sends a signal down the axon of a NANC nerve cell located in the penis. This causes NO to be released into the blood stream in the arteries of the penis.

One of the main roles of NO is to trigger the relaxation of the smooth muscle that lines the arteries. This leads to vasodilation and the lowering of blood pressure. In the penis this causes engorgement as the arteries expand and fill up with blood. The result is an erection that's stimulated by NO.

Nitric oxide acts locally. It diffuses into adjacent cells and binds to an enzyme called guanylyl cyclase. The binding of NO activates the enzyme, stimulating it to produce cyclic guanosine monophosphate or cGMP. The substrate for this reaction is guanosine triphosphate (GTP), a molecule that's similar to ATP except that the base is guanine instead of adenine.

ATP can be also be cyclized to form cAMP—a compound analogous to cGMP. cAMP is a common signal in many hormone-induced signal transduction pathways (and in creating a sense of smell). Like cAMP, cGMP is a signalling molecule. It activates specific enzymes that add phosphate to various proteins causing them to become more, or perhaps less, active. During an erection, the cGMP signal leads to changes in phosphorylation of muscle proteins causing the muscles to relax and the arteries to expand.

As you might expect, cGMP is not infinitely stable; otherwise a man might have an erection forever. cGMP is removed by the action of cGMP phosphodiesterase, which converts it to GMP. The turnover of cGMP in the penis is quite rapid leading to lack of signal unless NO is continually produced by the NANC nerve cells in order to replenish the supply of cGMP by reactivating guanylyl cyclase. This production of NO requires the attention of the brain, which has to keep focused on the task at hand.

The smooth muscle cells in the penis contain a special cGMP phosphodiesterase called phosphodiesterase-5 (PDE5). Sometimes the degradation of cGMP by PDE5 outpaces the production of cGMP by guanylyl cyclase. In such cases, the steady-state levels of cGMP aren't sufficient to signal muscle relaxation and no erection occurs. This is a common cause of erectile disfunction.

Viagra® works by inhibiting PDE5 thus blocking the breakdown of cGMP. This causes levels of cGMP to increase and an erection is prolonged. The structure of the PDE5 enzyme has been solved by Sung et al. (2003) in the presence of bound sildenafil (Viagra®) and two other inhibitors, tadalafil (Cialis®) and vardenafil (Levitra®). The structures are shown as stereo images in the figure below.

The upper image is the PDE5 proetin with overlapping molecules of sildenafil (red) and tadalfil (green) bound to the enzyme. The bottom images shown the structures of the three inhibitors. Viagra® binds to the site where cGMP would normally bind, thus blocking the degradation of cGMP. The structure of Viagra® is similar to cGMP and this exlains why it is such a potent inhibitor.

Sung B-J., Hwang, K.Y., Jeon, Y.H., Lee, J.I., Heo, Y.S., Kim, J.H., Moon, J., Yoon, J.M., Hyun, Y.L., Kim, E., Eum, S.J., Park, S.Y., Lee, J.O., Lee, T.G., Ro, S., and Cho, J.M. (2003) Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. Nature 425:98-102.

Multicellular Bacteria

PZ Myers posted an article on the evolution of multicellularity [The choanoflagellate genome and metazoan evolution]. He begins with ...

What are the key innovations that led to the evolution of multicellularity, and what were their precursors in the single-celled microbial life that existed before the metazoa? We can hypothesize at least two distinct kinds of features that had to have preceded true multicellularity.

The obvious feature is that cells must stick together; specific adhesion molecules must be present that link cells together, that aren't generically sticky and bind the organism to everything. So we need molecules that link cell to cell. Another feature of multicellular animals is that they secrete extracellular matrix, a feltwork of molecules outside the cells to which they can also adhere.

A feature that distinguishes true multicellular animals from colonial organisms is division of labor — cells within the organism specialize and follow different functional roles. This requires cell signaling, in which information beyond simple stickiness is communicated to cells, and signal transduction mechanisms which translate the signals into different patterns of gene activity.

PZ goes on to describe the genes in a single-cell eukaryote that diverged near the base of the animal phylum. The species is a choanoflagellate called Monosiga brevicollis.

It's important to note that this single-cell organism and its multicellular animal relatives form a distinct clade that is separated from the fungi and plants. Since there are multicellular fungi and multicellular plants, the evolution of multicellularity must have occurred many times.

PZ notes that choanoflagellates have primitive forms of adhesion molecules—one of the prerequisites for multicellularity in animals—but they lack some of the standard animal signalling pathways.

PZ Myers is a fan of evo-devo. There are many problems with this approach to biology but one of the most irksome is the emphasis on animals as models for all of evolution and development. I've referred to this as Animal Chauvinism. In his recent posting PZ is careful not to claim that the evolution of multicellularity in animals is the model for all forms of multicellular species but unsophisticated readers might easily get the wrong impression. Let's try and make the generalization that PZ might have wanted to make.

We can agree with his statement that two requirements of multicellularity are the ability of cells to stick together and the division of labor where cells differentiate to carry out specialized functions. Lest anyone imagines that these properties were invented by animals—or even by eukaryotes—let's look at some simple multicellular bacteria.

The first example is cyanobacteria. That's a filament of Anabaena sphaerica at the top of this posting. The cells adhere to each other through a common cell wall, forming long multicellular filaments. Other species of cyanobacteria form different groups of cells; for example, Glaucocystis (upper right) has four cells together in a single sheath.

Look carefully at the Anabaena filament. Do you see the fat round cell in the middle of the filament? That's a heterocyst. It's a differentiated cell that has become specialized for nitrogen fixation. All the other cells are capable of photosynthesis but the heterocyst specializes in fixing nitrogen. This species is a bacterial example of a multicellular organism with two types of cells.

The specialization of the heterocyst means that the two types of cells have to communicate. This communication takes place via small pores in the cell wall between the cells in the filament. Signaling involves transfer of small molecules such as ATP and glutamine between the various cells. What this means is that some cynaobacteria meet the two criteria that PZ Myers lays out for the evolution of multicellularity. There's no doubt about the fact that this version of a multicellular organism predates the evolution of metazoa by about 2-3 billion years.

The myxobacteria are dramatic example of multicellular bacteria. That's Chondromyces crocatus shown in the photograph above left.

Under certain conditions the single cells of myxobacteria come together to form fruiting bodies that consist of hundreds of cells. In the most extreme examples, some cells form the stalk, some cells form sprangia and others form spores. These are multicellular bacteria with specialized differentiated cells.

There are many other multicelluar bacteria but these two are sufficient to illustrate the point. Cell differentiation and multicellularity are not inventions of animals. There weren't even invented by eukaryotes. Differentiation and multicellularity were invented by bacteria long before the true eukaryotes ever appeared on this planet.

---

[Photo Credits: Anabaena sphaerica from Wikipedia: Glaucocystis from Cyanobacteria slides: Chondromyces crocatus from The Myxobacteria Web page]