Programming GPCR signalling within the endocytic network; mechanisms and therapeutic applications

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Cells communicate to each other by sending and responding to chemical messages. Coordinating this communication is essential for correct functioning of every organ in the body. These messages include photons of light, chemicals that we smell, the food that we eat, mineral ions such as calcium, hormones and neurotransmitters (chemical messengers of the brain). The chemical messages are received when they bind to specific proteins on the cell surface called receptors, which relay the message in to the cell. Our research is focussed on a family of receptors called G protein-coupled receptors (GPCRs). Our genes encode for more than 800 different kinds of GPCRs that are capable of responding to numerous different messages. Each organ in the body has many different GPCRs. Importantly, the function of these receptors is disrupted in various diseases and disorders, including cancer, obesity, diabetes, blindness, heart disease, depression, Parkinson's Disease, recurrent miscarriage and pre-term birth, to name but a few. Although many prescribed drugs target GPCRs, there is a high demand for new compounds that are more specific, have fewer side effects, and that are active for longer. Developing these new drugs requires an in-depth understanding of the molecular machinery that controls the activity these receptors.Once any cell receives external messages that bind to GPCRs, the activated receptors will relay specific signals to elicit an appropriate cellular response. This process is tightly controlled by the cell. One important mechanism is the rapid removal, or trafficking, of receptors from the cell surface in to interior compartments called endosomes, as a means of switching off these signals. However, we discovered that certain GPCRs recruited to specialized endosomes, which we termed very early endosomes (VEE), can switch on new signalling pathways. So, both duration and location of signals generated by GPCRs creates patterns that are critical for the cell, telling it whether to release more chemicals, activate particular genes, divide, or even die. If such signalling patterns are disrupted, or misdirected, they can lead to disease. However, our discovery also raises the possibility that drugs can be developed to redirect the receptor and change its function in a cell. The aim of this project is to understand how a cell controls receptor activity by examining the molecules involved in trafficking and signal decoding of GPCRs from the VEE. Our recent work also revealed that trafficking to the VEE of a GPCR important in reproduction and in early pregnancy (the LH receptor) may be important in how the uterus responds to hormones produced by the embryo in early pregnancy, and that these pathways may be altered in women suffering recurrent miscarriage. We will also assess the role of this compartment to other GPCRs by studying a receptor important in sensing carbohydrates in our food (the FFA2 receptor) and another that is targeted in IVF, cancer and menopause (the FSH receptor). For FSH and LH receptor we will determine whether drugs can alter the trafficking of specific GPCRs to the VEE or other endosomal compartments, and in turn impact on receptor activity. The outcome of this work will help us understand fundamental mechanisms of how cells communicate. As GPCRs are common drug targets, detailed knowledge of how GPCRs are regulated by the VEE may even provide new avenues for more effective treatments of a number of conditions that involve this superfamily of receptors.