Progress 07/01/99 to 06/30/05
Outputs
During this project my laboratory investigated the properties of several recently-identified GTPase-activating proteins (GAPs). The new information gained by our studies will be useful in understanding basic physiological processes that take place inside mammalian cells. Such information is a prerequisite for understand disease processes and for designing appropriate treatments for animal and human diseases.
Impacts
During this project we obtained significant new information regarding the cellular properties of GAPs and other related signaling proteins (e.g., AGS1, Rhes and other monomeric G proteins). Our data indicate that some of these proteins can profoundly influence the activity of voltage-gated calcium channels, which play essential roles in the functions of the cardiovascular and nervous systems. Specifically, our findings suggest that GAPs and related proteins may exert important cellular effects through their actions on calcium channels. This new information should contribute to an improved understanding of basic animal cell biology and thereby may ultimately be useful to veterinarians, physicians and biomedical researchers in understanding animal physiology. This improved understanding may form the basis for medical advances in the prevention and treatment of disease. Thus, our findings have the potential to contribute to improved health and economic well being.
Publications
- No publications reported this period
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Progress 01/01/04 to 12/31/04
Outputs
We have made significant experimental progress during the past year. Specifically, we have examined the signaling functions of several different GTPase-activating proteins (GAPs) including RGS3, p115RhoGEF and GRK2RGS. We have also greatly expanded our ongoing study of the recently-discovered Activator of G protein Signaling 1 protein (AGS1). This work also includes several other proteins that are closely related to AGS1 and that like AGS1 have unknown physiological functions. Most of our experiments have focused on the role that GAPs and AGS1 play in regulating the activity of voltage-gated calcium channels. During the past year, we obtained significant new results that will be very helpful in understanding the cellular functions of these proteins. Our recent results are currently being prepared for publication in two full-length manuscripts. These manuscripts will likely appear in peer-reviewed journals during 2005.
Impacts
As a result of this project, we have obtained significant new information regarding the cellular properties of GAPs and other related signaling proteins (e.g., AGS1). Specifically, our preliminary data reveal that these proteins can profoundly influence the activity of voltage-gated calcium channels, which play essential roles in the functions of the cardiovascular and nervous systems. Our findings suggest that GAPs and related proteins may exert important cellular effects through their actions on calcium channels. This new information contributes to an improved understanding of cell biology and thereby may ultimately be useful to veterinarians, physicians and biomedical researchers in understanding animal physiology. This improved understanding may form the basis for medical advances in the prevention and treatment of disease. Thus, our findings have the potential to contribute to improved health and economic well being.
Publications
- Bannister, R.A. 2003. Muscarinic modulation of neuronal voltage-gated calcium channels. Ph.D. dissertation. Department of Biology, Utah State University.
- Bannister, R.A., U. Meza, and B.A. Adams. 2004. Phosphorylation-Dependent Regulation of Voltage-gated Ca2+ Channels. Chapter 10, In: Voltage-gated Calcium Channels, edited by G. Zamponi. Landes Bioscience, available at: http://www.eurekah.com/abstract.php.
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Progress 01/01/03 to 12/31/03
Outputs
Significant progress was made during the fourth year of the project. We completed a structure-function analysis of two GTPase-activating proteins, RGS2 and RGS4. Results from this work are currently being analyzed and will be submitted for publication during early 2004. We also completed an initial study of the novel signaling protein AGS1. Results from this second study have already been submitted for publication. A third manuscript concerning a voltage-gated Ca2+ channel that interacts with GTPase-activating proteins has been accepted for publication and is currently in press (see Publications).
Impacts
Information revealed by this project has potential relevance for understanding the molecular bases of diseases that affect humans and other animals.
Publications
- Bannister, R.A., K. Melliti and B.A. Adams. 2004. Differential modulation of CaV2.3 Ca2+ channels by Gaq/11-coupled muscarinic receptors. Molecular Pharmacology volume 65 (February 2004 issue).
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Progress 01/01/02 to 12/31/02
Outputs
Considerable progress was made during the third year of the project. We were successful in reconstituting slow, muscarinic inhibition of neuronal L-type calcium channels in a mammalian cell line, and in characterizing the effects of two GAPs (RGS2 and RGS4) on this signaling pathway. Furthermore, we were able to obtain significant new insights into the physiological role of a recently identified signaling protein (AGS-1).
Impacts
Our experimental results provide new insights into the properties of RGS proteins and AGS proteins. These insights will be useful in completely understanding cell signaling pathways in mammals. A complete understanding of cell signaling pathways is essential for the rational design of drugs and other therapies used to treat various animal diseases. Furthermore, our findings provide enhanced understanding of neuronal L-type calcium channels, which perform essential roles in hearing, secretion of insulin, and cardiac function.
Publications
- Bannister, R.A., K. Melliti and B.A. Adams. 2002. Reconstituted slow muscarinic inhibition of neuronal L-type (CaV1.2c) Ca2+ channels. Biophysical Journal 83(6): 3256-3267.
- Bannister, R.A., U. Meza and B.A. Adams. 2002. Phosphorylation-dependent regulation of voltage-gated Ca2+ channels. Chapter 11. In Voltage-gated Calcium Channels, edited by G. Zamponi. Landes Bioscience.
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Progress 01/01/01 to 12/31/01
Outputs
Significant progress was made during the second year of the project. Our experimental results have shown that Regulator of G protein Signaling protein 2 (RGS2) can block slow muscarinic inhibition of neuronal N-type calcium channels while leaving fast muscarinic inhibition of these channels intact.
Impacts
N-type calcium channels are essential for neurotransmission in the brain. Muscarinic inhibition of N-type calcium channels has profound effects upon brain function. Our new findings have important implications for understanding the functional roles that RGS proteins play in the mammalian brain.
Publications
- Melliti, K., U. Meza and B. Adams. 2001. RGS2 blocks slow muscarinic inhibition of N-type Ca2+ channels reconstituted in a human cell line. Journal of Physiology 532:337-347.
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Progress 01/01/00 to 12/31/00
Outputs
Significant progress was made during the first year of the project. Our experiments revealed an interesting property of GTPase-activating proteins (GAPs) that is likely to have important implications for understanding their functions in vivo. Specifically, we found that two kinds of RGS proteins (RGS2 and RGS8) can function primarily as effector antagonists rather than as GAPs in living cells. As effector antagonists, RGS proteins specifically block signaling by Galpha-q while leaving intact signaling by its associated Gbeta-gamma subunit. Similar findings were obtained for the carboxyl-terminus region of phospholipase C-beta 1, which can also bind Galpha-q and which has also been previously shown to act as a GAP.
Impacts
Understanding animal diseases requires knowledge of normal physiological processes. Our findings increase understanding of normal cell physiology. Thus, our results may have widespread impact by contributing toward prevention or treatment of animal diseases caused by errors of cellular metabolism.
Publications
- Melliti, K., U. Meza and B. Adams. 2000. Muscarinic stimulation of neuronal a1E Ca channels is selectively blocked by the effector antagonist function of RGS2 and PLCb1. Journal of Neuroscience 20:7167-7173.
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