Grant: Operating Grant

The conversion of fuel molecules such as glucose into the main source of biochemical energy, adenosine 5'-triphosphate (ATP), generates waste products such as carbon dioxide, protons and other weak acids (i.e., lactic acid) or bases (i.e., bicarbonate) that must be efficiently removed or buffered to sustain a suitable acid-base (pH) milieu for stable protein activity and interactions, and ultimately the function and survival of all living organisms. Regulation of pH is mainly achieved by a variety of ion transport proteins present in cell membranes that can selectively move these waste products from one side of the membrane to the other for disposal or for reuse in other cellular processes. This research proposal is focused on the study of one specific group of pH-regulating transporters called sodium/proton exchangers (NHEs). The NHE gene family contains 11 structurally-related members. Disruptions in the normal functioning of some of these genes have previously been linked to different human diseases, including hypertension, heart attacks, stroke, and chronic diarrhea. In this particular proposal, we are focusing on two poorly studied members NHE6 and NHE9 that are located inside most cells in small membrane vesicles called recycling endosomes. Recent studies have identified mutations in these genes that cause mental retardation, autism and attention deficit disorders. We have isolated the NHE6 and NHE9 genes and are currently studying the effect the mutated genes have on recycling endosomal function. We hypothesize that these defects impair the pH and movement of recycling endosomes that carry neurotransmitter receptors to synapses of neurons, which in turn affects brain electrical activity and function. This research proposal will test this assumption using sophisticated techniques in molecular & cellular biology as well as electrophysiology; thereby shedding new insights into their physiological contributions to human health, disease and treatment.