HIGH-THROUGHPUT SCREENS FOR G PROTEIN-COUPLED RECEPTORS

Background: G protein–coupled receptors (GPCRs) communicate extracellular signals to intracellular G proteins that transduce and amplify the signals. In mammals, it is believed that there are over 1000 GPCRs. Of those, several hundred are likely to be involved with various disease processes and thus are potential diagnostic and/or therapeutic targets. The majority of GPCRs activate G proteins that modulate cyclic AMP pathways, which unfortunately are not particularly amenable to large-scale screening methods. Furthermore, while the detection of calcium released by the phospholipase C pathway activated by certain G proteins is amenable to high-throughput or robotic screening methods, the GPCRs that activate these G proteins are relatively scarce.

Description: Researchers at the Gladstone Institutes have created several G protein constructs that activate the phospholipase C pathway in response to various GPCRs that normally activate other pathways, such as the cAMP pathway. This provides a rapid means (less than 60 seconds) for identifying modulators of an increased number and variety of GPCRs by detecting the increased calcium levels using high-throughput screening methods. Examples of this technology are presented in J. Biol. Chem. 272:19107, 1997.

Applications: Among the physiological responses involving signal transduction via GPCRs are the dilation/constriction of blood vessels, bronchi and organs within the gastrointestinal tract, the modulation of endocrine secretions, and the control of heart rate. This technology accelerates the screening for modulators (including agonists and antagonists) of GPCRs and, thus, has tremendous potential for the development of new diagnostics and therapeutics.

Advantages: The Gladstone technology provides a rapid method (less than 60 seconds) to identify modulators of an increased number and variety of GPCRs.

The method is:

• Amenable to high-throughput screening, reducing the time and labor of the screening process.
• Capable of screening an increased variety of GPCRs, especially the large number of those modulating cAMP pathways.

Reference: 1997-294

Patent Status: US Patent 6,383,761

Gladstone Contact: Caryl Cachola
Telephone: 415-734-2082

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