Signal transducing synaptic molecules and uses thereof

Details Signal transducing synaptic molecules and uses thereof Signal transducing synaptic molecules and uses thereof

1999-04-19

2004-04-20

Nolan, Patrick J. (Department: 1644)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

Reexamination Certificate

active

06723838

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to signal transducing synaptic molecules and particularly to mammalian SYNGAP (
Syn
aptic
G
TPase
A
ctivating
P
rotein), including recombinant SYNGAPs and fragments and derivatives thereof. In one aspect, the invention provides molecules for detecting and analyzing SYNGAPs in vitro and in vivo. In another aspect, the invention provides assays for detecting compounds that modulate SYNGAP or SYNGAP-related activities. The invention has a variety of applications including use in screens to detect pharmacological agents useful in the diagnosis or treatment of disorders associated with SYNGAP.
2. Background
Neurons communicate by a variety of means including synaptic transmission. One form of synaptic transmission involves chemical signaling; a process generally involving neurotransmitter release from one neuron and modulation of a post-synaptic receptor in another neuron. The release and modulation is usually manifested by propagation of a chemical or electrical impulse. See Edelman, G. M. et al. (eds.) (1987) in
Synaptic Function
, New York: Wiley; and Goodman and Gilman (1996) in
The Pharmacological Basis of Therapeutics
, 9
th
ed. J. G. Hardman, et al. (eds) Pergamon Press, NY.
In many instances, chemical signaling requires specialized neuronal structures called chemical synapses. Analysis of chemical synapses has attracted substantial interest. For example, chemical synapses have been reported to be involved in many, if not all, nervous system functions including neuronal plasticity. In particular, neuronal plasticity is believed to impact critical functions such as cognition, e.g., memory and learning, as well as certain neurodegenerative disorders. See e.g., Kandel, E. R. et al; (1991) in
Principles of Neuroscience
, Appleton & Lange, Norwalk, Conn. and references cited therein.
A variety of approaches have been used in attempts to understand chemical synapses. For example, certain molecular and biochemical approaches have suggested that chemical synapses are structured and include molecules such as receptors, cytoskeletal proteins, and signal transduction molecules. See e.g., Ehlers, M. D., et al. (1996)
Curr. Opin. Cell Biol
. 8: 484; Sheng, M. (1996)
Neuron
17:575; and Huganir, R. L. and Greengard, M. (1990)
neuron
5: 555.
More particularly, it has been reported that appropriate chemical synapse structure requires presence of a protein termed PSD-95/SAP90. The PSD-95/SAP90 protein is representative of a family of molecules including SAP120. Specific members of the PSD-95/SAP90 family are localized at or near chemical synapses. See e.g., Ehlers, M. D., et al. supra; Sheng, M supra; Lau, L. F., et al. (1996)
J. Biol. Chem
. 271:21622; Muller, B. M., et al. (1996)
Neuron
17:255; and references cited therein.
There has much effort towards understanding PSD-95/SAP90 and related proteins. For example, it has been reported that most members of the protein family exhibit the same or a closely related structure, i.e., three tandem PDZ (
P
SD-95,
D
LG,
Z
O-1) domains, a SH3 (src homology 3) domain, and an inactive yeast guanylate kinase domain (GK). See e.g., Kim, E., et al. (1995)
Nature
378:85; Kornau, H. C., et al. (1995)
Science
269:1737.
There has been recognition that PDZ domains exist in proteins associated with cell membranes. For example, it has been reported that the PDZ domains of PSD-95 bind to specific subunits of the (N-methyl-D-aspartate) NMDA receptor. It has also been reported that the last three amino acids of the NMDA receptor subunits define a consensus sequence (T/SXV; X is any amino acid). The subunit sequence has been reported to facilitate the binding. See e.g., Kennedy, M. B. (1995)
Trends Biochem. Sci
. 20; Gomperts, S. N. (1996)
Cell
84:659; Sheng, M. supra.
There has also been recognition that chemical synapses can employ signal transduction to modulate pre- and post-synaptic activity. For example, certain members of the PSD-95/SAP90 protein family are believed to be associated with signal transduction. More particularly, the PSD-95 protein has been proposed to interact with certain signal transduction kinases. That interaction has been proposed to be important to synaptic function. See Gomperts, supra; Saras, J., and Heldin, C. H. (1996)
Trends Biochem. Sci
. 21:455; Huganir, R. L. and Greengard, M. supra.
There has also been recognition that the PSD-95/SAP90 protein may be capable of serving as an adaptor molecule. More specifically, there have been reports that the PSD-95/SAP90 protein may be able to relate synaptic activity and signal transduction in some instances. That property is believed to important to appropriate synapse function. See e.g., Brenman, J. E. et al. (1996)
Cell
84: 757; and Saras, J. and Heldin, Carl-Henrik (1996), supra.
A variety of signal transduction molecules are known including specified kinases and proto-oncogenes. For example, the proto-oncogene Ras is recognized as a G-protein that is apparently involved in signal transduction pathways affecting, e.g., cell growth, cell differentiation, neuronal plasticity and cell survival. In particular, Ras appears to have a substantial role in kinase activation. In addition, biological activity manifested by a variety of neurotrophic factors (i.e. neurotrophins) may be derived through Ras-associated signaling pathways. See e.g., Bokoch, G. M., and Der, C. J. (1993)
FASEB. J
. 7:750; Marshall, C. J. (1996)
Cell Biol
. 8:197; Finkbeiner, S. and Greenberg, M. E. (1996)
Neuron
16:233; Kang, H., and Schuman, E. M. (1996)
Science
273:1402.
Certain neuronal functions have been proposed to be affected by Ras-mediated signal transduction. See e.g., Seger, R., and Krebs, E. G. (1995)
FASEB J
. 9:726; and Finkbeiner and Greenberg, supra.
Additional signal transduction pathways are known. For example, the inositol triphosphate signaling pathway has been reported to couple modulation of certain receptors to a variety of functions, many of which relate to calcium. See e.g., Berridge, M. J. (1988)
Pro. R. Soc. Lond
. (
Biol
) 234: 359.
It would be desirable to identify molecules that impact chemical synapse function and particularly interact with the PSD-95/SAP90 protein. It would be further desirable to identify molecules that can bind the PSD-95/SAP90 protein and affect signal transduction. It would also be desirable to have effective assays for identifying compounds and especially pharmaceutical agents with capacity to modulate the function of these molecules.
SUMMARY OF THE INVENTION
The present invention features molecules that relate to SYNGAP (
Syn
aptic
G
TPase
A
ctivating
P
rotein); an excitatory synapse protein that has been found to bind synaptic proteins and modulate signal transduction. In one aspect, the invention provides isolated polynucleotides that encode SYNGAP or fragments or derivatives thereof Further provided are SYNGAP or SYNGAP-related polypeptide encoded by the polynucleotides. In another aspect, the invention provides immunological molecules that are capable of binding the polypeptides. Additionally provided are methods for using the molecules of this invention, e.g., to treat or prevent at least one disorder mediated by SYNGAP. The invention also provides screening assays for detecting compounds useful in the diagnosis or treatment of disorders impacted by SYNGAP.
We have discovered mammalian SYNGAP: a novel protein that binds synaptic proteins important for chemical synapse function. Additionally, we have found that SYNGAP is capable of modulating certain signal transduction molecules and particularly the Ras proto-oncogene (Ras). We have particularly found that SYNGAP is positioned to relate synaptic activity and signal transduction, thereby indicating a significant role in many aspects of nervous system function.
As will be discussed below, SYNGAP is represented by a family of alternatively spliced variants including SYNGAP-a, SYNGAP-b, and SYNGAP-c.
The present invention provides a number of significant uses and advantages. For example, the inventi

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