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Abstract/Syllabus:
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Kota, Parvathi, 7.342 G-Protein Coupled Receptors: Vision and Disease, Spring 2007. (Massachusetts Institute of Technology: MIT OpenCourseWare), http://ocw.mit.edu (Accessed 07 Jul, 2010). License: Creative Commons BY-NC-SA
Crystal structure of rhodopsin. Rhodopsin, a dim-light photoreceptor located in the retina, serves as a model for G-protein coupled receptors. (PDB ID: 1f88. Palczewski, K., T. Kumasaka, T. Hori, C. A. Behnke, H. Motoshima, B. A. Fox, I. L. Trong, D. C. Teller, T. Okada, R. E. Stenkamp, M. Yamamoto, and M. Miyano. "Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor." Science 289 (2000): 739-745. Image courtesy of the Research Collaboratory for Structural Bioinformatics. Berman, H. M., J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H. Weissig, I. N. Shindyalov, and P. E. Bourne. "The Protein Data Bank." Nucleic Acids Research 28 (2000): 235-242.)
Course Description
How do we communicate with the outside world? How are our senses of vision, smell, taste and pain controlled at the cellular and molecular levels? What causes medical conditions like allergies, hypertension, depression, obesity and various central nervous system disorders? G-protein coupled receptors (GPCRs) provide a major part of the answer to all of these questions. GPCRs constitute the largest family of cell-surface receptors and in humans are encoded by more than 1,000 genes. GPCRs convert extracellular messages into intracellular responses and are involved in essentially all physiological processes. GPCR dysfunction results in numerous human disorders, and over 50% of all prescription drugs on the market today directly or indirectly target GPCRs.
In this course, we will discuss GPCR signal transduction pathways, GPCR oligomerization and the diseases caused by GPCR dysfunction. We will study the structure and function of rhodopsin, a dim-light photoreceptor and a well-studied GPCR that converts light into electric impulses sent to the brain and leads to vision. We will also discuss how mutations in rhodopsin cause retinal degeneration and congenital night blindness.
This course is one of many Advanced Undergraduate Seminars offered by the Biology Department at MIT. These seminars are tailored for students with an interest in using primary research literature to discuss and learn about current biological research in a highly interactive setting. Many instructors of the Advanced Undergraduate Seminars are postdoctoral scientists with a strong interest in teaching.
Syllabus
Prerequisites
Background in Biology and/or Chemistry.
Overview
How do we communicate with the outside world? How are our senses of vision, smell, taste and pain controlled at the cellular and molecular levels? What causes medical conditions like allergies, hypertension, depression, obesity and various central nervous system disorders? G-protein coupled receptors (GPCRs) provide a major part of the answer to all of these questions. GPCRs constitute the largest family of cell-surface receptors and in humans are encoded by more than 1,000 genes. GPCRs convert extracellular messages into intracellular responses and are involved in essentially all physiological processes. GPCR dysfunction results in numerous human disorders, and over 50% of all prescription drugs on the market today directly or indirectly target GPCRs. In this course, we will discuss GPCR signal transduction pathways, GPCR oligomerization and the diseases caused by GPCR dysfunction. We will study the structure and function of rhodopsin, a dim-light photoreceptor and a well-studied GPCR that converts light into electric impulses sent to the brain and leads to vision. We will also discuss how mutations in rhodopsin cause retinal degeneration and congenital night blindness.
Format
The course is a weekly seminar based on the primary scientific literature concerning G-protein coupled receptors. The main goal of this course is to familiarize students with the critical reading, analysis and discussion of scientific papers. We will discuss two papers each. The papers must be read before coming to the class. You will be expected to send me via email one or two discussion questions by the morning of the class. You are expected to actively engage in class discussions. Each class will conclude with a short introduction to the papers to be presented in the next class.
We will visit on-campus Atomic Force Microscopy Facility. We will also have a field trip to a biotechnology company in the Cambridge area.
Grading
Attendance is central to this course. No more than one class can be missed. If you do miss a class, we will arrange a make-up assignment, for example a one-page summary of the paper discussed in that particular class.
This course will be graded pass/fail. Active participation in class discussion, completion of the assignments and attendance will result in a passing grade.
Calendar
Course calendar.
SES # |
TOPICS |
1 |
Introduction |
2 |
G-Protein coupled receptors and rhodopsin |
3 |
Visual cascade part I - Activation of rhodopsin by light |
4 |
Visual cascade part II - Rhodopsin and G protein (transducin) interaction |
5 |
Visit to an Atomic Force Microscopy Facility |
6 |
Rhodopsin dimerization |
7 |
Rhodopsin mutations, retinal degeneration and night blindness |
8 |
Field trip to the Novartis Institutes for BioMedical Research |
9 |
Drug addiction - Dopamine receptors and activation mechanism |
10 |
Allergies - Histamine receptors |
11 |
How do mutations in chemokine receptors inhibit CCR5-mediated HIV infection? |
12 |
Sense of smell: Olfactory receptors |
13 |
Sense of taste: Taste receptors |
14 |
Oral presentations: General discussion and future perspectives |
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Further Reading:
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Readings
Course readings.
SES # |
TOPICS |
READINGS |
1 |
Introduction |
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2 |
G-protein coupled receptors and rhodopsin |
Unger, V. M., P. A. Hargrave, J. M. Baldwin, and G. F. X. Schertler. "Arrangement of Rhodopsin Transmembrane α-helices." Nature 389 (1997): 203-206.
Palczewski, K., T. Kumasaka, T. Hori, C. A. Behnke, H. Motoshima, B. A. Fox, I. L. Trong, D. C. Teller, T. Okada, R. E. Stenkamp, M. Yamamoto, and M. Miyano. "Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor." Science 289 (2000): 739-745.
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3 |
Visual cascade part I - Activation of rhodopsin by light |
Zhukovsky, E. A., and D. D. Oprian. "Effect of Carboxylic Acid Side Chains on the Absorption Maximum of Visual Pigments." Science 246 (1989): 928-930.
Farrens, D. L., C. Altenbach, K. Yang, W. L. Hubbell, and H. G. Khorana. "Requirement of Rigid-body Motion of Transmembrane Helices for Light Activation of Rhodopsin." Science 274 (1996): 768-770.
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4 |
Visual cascade part II - Rhodopsin and G protein (transducin) interaction |
Weiss, E. R., D. J. Kelleher, and G. L. Johnson. "Mapping Sites of Interaction between Rhodopsin and Transducin Using Rhodopsin Antipeptide Antibodies." J Biol Chem 263 (1988): 6150-6154.
Natochin, M., M. Moussaif, and N. O. Artemyev. "Probing Mechanism of Rhodopsin-catalyzed Transducin Activation." J Neurochem 77 (2001): 202-210.
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5 |
Visit to an Atomic Force Microscopy Facility |
Fotiadis, D., S. Scheuring, S. A. Müller, A. Engel, and D. J. Müller. "Imaging and Manipulation of Biological Structures with the AFM." Micron 33 (2002): 385-397.
Field trip schedule (PDF)
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6 |
Rhodopsin dimerization |
Fotiadis, D., Y. Liang, S. Filipek, D. A. Saperstein, A. Engel, and K. Palczewski. "Rhodopsin Dimers in Native Disc Membranes." Nature 421 (2003): 127-128.
Liang, Y., D. Fotiadis, S. Filipek, D. A. Saperstein, K. Palczewski, and A. Engel. "Organization of the G Protein Coupled Receptors Rhodopsin and Opsin in Native Membranes." J Biol Chem 278 (2003): 21655-21662.
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7 |
Rhodopsin mutations, retinal degeneration and night blindness |
Sung, C. H., B. G. Schneider, N. Agarwal, D. S. Papermaster, and J. Nathans. "Functional Heterogeneity of Mutant Rhodopsins Responsible for Autosomal Dominant Retinitis Pigmentosa." Proc Natl Acad Sci 88 (1991): 8840-8844.
Jin, S., M. C. Cornwall, and D. D. Oprian. "Opsin Activation as a Cause of Congenital Night Blindness." Nature Neuroscience 6 (2003): 731-735.
Pulse-Chase experiment
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8 |
Field trip to the Novartis Institutes for BioMedical Research |
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9 |
Drug addiction - Dopamine receptors and activation mechanism |
Lee, S. P., C. H. So, A. J. Rashid, G. Varghese, R. Cheng, A. J. Lanca, B. F. O'Dowd, and S. R. George. "Dopamine D1 and D2 Receptor Co-activation Generates a Novel Phospholipase C-mediated Calcium Signal." J Biol Chem 279 (2004): 35671-35678.
Guo, W., L. Shi, M. Filizola, H. Weinstein, and J. A. Javitch. "Crosstalk in G Protein-coupled Receptors: Changes at the Transmembrane Homodimer Interface Determine Activation." Proc Natl Acad Sci 102 (2005): 17495-17500.
Dopamine receptors
Molecular mechanism of drug addiction
D1/D2 synergism
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10 |
Allergies - Histamine receptors |
Morisset, S., A. Rouleau, X. Ligneau, F. Gbahou, J. Tardivel-Lacombe, H. Stark, W. Schunack, C. R. Ganellin, Schwartz, and J-M. Arrang. "High Constitutive Activity of Native H3 Receptors Regulates Histamine Neurons in Brain." Nature 408 (2000): 860-864.
Gillard, M., C. Van Der Perren, N. Moguilevsky, R. Massingham, and P. Chatelain. "Binding Characteristics of Cetirizine and Levocetirizine to Human H1 Receptors: Contribution of Lys191 and Thr194." Mol Pharmacol 61 (2002): 391-399.
Milligan, G., R. A. Bond, and M. Lee. "Inverse Agonism: Pharmacological Curiosity or Potential Therapeutic Strategy?" Trends in Pharmacological Sciences 16, no. 1 (January 1995): 10-13.
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11 |
How do mutations in chemokine receptors inhibit CCR5-mediated HIV infection? |
Benkirane, M., D-Y Jin, R. F. Chun, R. A. Koup, and K-T Jeang. "Mechanism of Transdominant Inhibition of CCR5-mediated HIV-1 Infection by ccr5d32." J Biol Chem 272 (1997): 30603-30606.
Hernanz-Falcon, P., J. M. Rodriguez-Frade, A. Serrano, D. Juan, A. D. Sol, S. F. Soriano, F. Roncal, L. Gomez, A. Valencia, C. Martinez-A, and M. Mellado. "Identification of Amino Acid Residues Crucial for Chemokine Receptor Dimerization." Nature Immunology 5 (2004): 216-223.
Supplementary material for Hernanz-Falcon, et al
Flow cytometry
Yeast two hyrbid system
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12 |
Sense of smell: Olfactory receptors |
Buck, L., and R. Axel. "A Novel Multigene Family May Encode Odorant Receptors: Molecular Basis for Odor Recognition." Cell 65 (1991): 175-187.
Oka, Y., M. Omura, H. Kataoka, and K. Touhara. "Olfactory Receptor Antagonism between Odorants." EMBO J 23 (2004): 120-126.
Techniques used in the papers:
- Southern blot
- Northern blot
- DNA hybridization
- Expression screening
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13 |
Sense of taste: Taste receptors |
Nelson, G., M. A. Hoon, J. Chandrashekar, Y. Zhang, N. J. P. Ryba, and C. S. Zuker. "Mammalian Sweet Taste Receptors." Cell 106 (2001): 381-390.
Moon, S. J., M. Köttgen, Y. Jiao, H. Xu, and C. Montell. "Taste Receptor Required for the Caffeine Response in Vivo." Current Biology 16 (2006): 1812-1817.
———. "Supplemental Data: Taste Receptor Required for the Caffeine Response in Vivo." Current Biology 16 (2006): 1812-1817.
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14 |
Oral presentations: General discussion and future perspectives |
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