Allosteric Modulation of G Protein-Coupled Receptors

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The normal function of all living cells depends on how they respond to the multitude of physical and chemical stimuli to which they are constantly exposed. The majority of chemical stimuli acting on cells do so not by directly entering the cell, but rather by acting on specific types of receiver proteins on the cell's surface called receptors. One important family of receptors transmit their message to the inside of the cell by coupling to yet another type of protein known as the G protein. Aberrations in the normal function of these G protein-coupled receptors have been implicated in a wide variety of disorders, including neuropsychiatric conditions, endocrine disorders, cardiovascular disease and many cancers. To date, the majority of drugs acting at G protein-coupled receptors do so by binding to specific regions on these receptors. Although many breakthroughs in disease treatment have been achieved using this approach, there remain a number of acknowledged limitations, including lack of drug selectivity, toxicity and reduced responsiveness with prolonged therapy. Our current proposal focuses on targeting drugs to alternative regions of G protein-coupled receptors that may overcome many of the limitations associated with current drug therapies. An understanding of the properties of these alternative drug binding sites, which will be investigated in our current grant, can lead to more effective treatments for a variety of diseases.