BIO254:Gprotein: Difference between revisions
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===Discovery=== | ===Discovery=== | ||
The role of cAMP-dependent signal transduction was known in the 1950s and 1960s; however, the essential role of GTP was masked by the fact that cAMP preparations were contaminated by GTP (Milligan, 2006). In the 1970s a mutated cell line was found to have an intact ligand receptor and amplifier, yet this cell line did not respond to the receptors ligand (Fig. 3), implying the existence of an intermediary and also providing a cell line on which reconstitution assays could be performed. Alfred G. Gilman purified and identified this intermediary in 1980 (Northup, 1980) by reconstituting the complete pathway by adding a purified protein, the G-protein. [[Image: NobelA. | The role of cAMP-dependent signal transduction was known in the 1950s and 1960s; however, the essential role of GTP was masked by the fact that cAMP preparations were contaminated by GTP (Milligan, 2006). In the 1970s a mutated cell line was found to have an intact ligand receptor and amplifier, yet this cell line did not respond to the receptors ligand (Fig. 3), implying the existence of an intermediary and also providing a cell line on which reconstitution assays could be performed. Alfred G. Gilman purified and identified this intermediary in 1980 (Northup, 1980) by reconstituting the complete pathway by adding a purified protein, the G-protein. [[Image: NobelA.gif|frame|center|Figure 3a. Image modified from http://nobelprize.org/nobel_prizes/medicine/laureates/1994/illpres/disc-gprot.html.]][[Image: NobelB.gif|frame|center|Figure 3b. Image modified from http://nobelprize.org/nobel_prizes/medicine/laureates/1994/illpres/disc-gprot.html.]] | ||
The heterotrimeric G protein that Gilman isolated increased cAMP levels. In 1980 Martin Rodbell wrote a review (Rodbell, 1980) that helped direct the search for the first cAMP reducing G-protein to be discovered, in 1984. Martin Rodbell and Alfred G. Gilman were awarded the 1994 Nobel Prize in Physiology and Medicine for the discovery of "G-proteins and the role of these proteins in signal transduction in cells". Since the first G-proteins were identified, many others with effectors other than cAMP have been cloned, in many cases by homology. Currently 16 alpha, 5 beta, and 14 gamma subunits have been identified (Milligan, 2006). | The heterotrimeric G protein that Gilman isolated increased cAMP levels. In 1980 Martin Rodbell wrote a review (Rodbell, 1980) that helped direct the search for the first cAMP reducing G-protein to be discovered, in 1984. Martin Rodbell and Alfred G. Gilman were awarded the 1994 Nobel Prize in Physiology and Medicine for the discovery of "G-proteins and the role of these proteins in signal transduction in cells". Since the first G-proteins were identified, many others with effectors other than cAMP have been cloned, in many cases by homology. Currently 16 alpha, 5 beta, and 14 gamma subunits have been identified (Milligan, 2006). | ||
===G Protein-Coupled Receptors=== | ===G Protein-Coupled Receptors=== | ||
Revision as of 08:41, 27 October 2006
Introduction
The term G protein refers to proteins that bind the nucleotide guanine as guanosine triphosphate (GTP) and guanosine diphosphate (GDP). There are two types of G proteins: heterotrimeric, or large, G proteins and small G proteins. Heterotrimeric G proteins are membrane-associated and, along with G protein-coupled receptors (GPCRs), function primarily in cell signalling and signal transduction. Small GTP-binding proteins function in diverse cellular processes including signal transduction, cytoskeletal reorganization, and vesicle trafficking. The small G protein superfamily includes the Ras family (signal transduction), the Rho/Rac family (cytoskeleton), the Rab and Sar1/Arf families (vescicle trafficking), and the Ran family (nuclear import/export) (Takai et al., 2001).
A molecular switch
Heterotrimeric G proteins are unique in that they exist as a complex (Gαβγ) in the GDP-bound state but dissociate (into Gα and Gβγ) upon the release of GDP/binding of GTP.
Heterotrimeric G proteins
Discovery
The heterotrimeric G protein that Gilman isolated increased cAMP levels. In 1980 Martin Rodbell wrote a review (Rodbell, 1980) that helped direct the search for the first cAMP reducing G-protein to be discovered, in 1984. Martin Rodbell and Alfred G. Gilman were awarded the 1994 Nobel Prize in Physiology and Medicine for the discovery of "G-proteins and the role of these proteins in signal transduction in cells". Since the first G-proteins were identified, many others with effectors other than cAMP have been cloned, in many cases by homology. Currently 16 alpha, 5 beta, and 14 gamma subunits have been identified (Milligan, 2006).
G Protein-Coupled Receptors
For more information on G protein-coupled receptors, see the GPCR wikipedia entry
Families
The original GPCR cell signaling pathway described included Gs proteins. Gαs, among other things, activates adenylate cyclase. Gi pathways are characterized by the ability of Gαi to inhibit adenylate cyclase, and of Gβγ to activate its own downstream effectors, which include phosphatidylinositol 3-kinase (PI3K). The Gq pathway is activated by calcium-mobilizing hormones and acts through inositol trisphosphate (IP3), diacylglycerol (DAG), and protein kinase C (PKC). The G12/13 family is the most recently identified and the least well studied. It is not known as to what extent Gα12 and Gα13 act through distinct effectors (Neves, 2002).
The Rho/Rac family of small GTPases
References
1. Takai Y, Sasaki T, Matozaki T. Small GTP-Binding Proteins. Physiol Rev. 81, 153-208 (2001).
2. Luo L. Rho GTPases in neuronal morphogenesis Nat Rev Neurosci. 1, 173-180 (2000).
3. Milligan G, Kostenis E. Heterotrimeric G-proteins: a short history. Br J Pharmacol. 147 Suppl 1:S46-55 (2006)
4. Firestein, S. How the olfactory system makes sense of scents. Nature 413, 211-218 (2001)
5. Neves S, Ram P, Iyengar R. G protein pathways. Science 296, 1636-1639 (2002)
6. Huber A, Kolodkin A, Ginty D, Cloutier JF. Signaling at the growth cone: ligand-receptor complexes and the control of axon growth and guidance. Ann Rv Neurosci 26, 509-63 (2003)
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