Discovery and function of ion channels in liver epithelia.

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My research program is focused on the identification and roles of ion channels in the physiology of the liver. Our current focus is on a Transient Receptor Potential Melastatin (TRPM) channel, isoform 7. TRPM7, a ubiquitously expressed channel-kinase, is associated with survival of many proliferating cells; knock-out is embryonic lethal. Recent studies support a significant role for TRPM7 in organogenesis. We showed that TRPM7 channel activity is significantly higher in dividing liver cells than in terminally differentiated, non-dividing adult hepatocytes. Channel block caused higher death rates in dividing as compared with adult cells, implying a fundamental role for Mg2+ influx in supporting liver cell proliferation. We also localized TRPM7 to the nuclear envelope in all liver cells in addition to the established cytosolic, punctate expression seen in other cells. TRPM7 expression was higher in the nuclear envelope of non-dividing adult hepatocytes as compared with dividing cells. Differentiating conditions reduced channel activity and increased nuclear envelope TRPM7 in dividing cells. During mitosis TRPM7 associates with the mitotic spindle. Thus TRPM7 channel activity seems to be important in embryonic hepatocyte expansion and hepatoma cell survival, whereas nuclear envelope accumulation is associated with terminal differentiation. Over the next five years we will define how TRPM7 supports embryonic hepatocyte expansion and de-differentiated growth, and terminal differentiation. A spectrum of rat hepatocytes from dividing embryonic and hepatoma cells to non-dividing adult cells will be used. These cells provide unique opportunities to study TRPM 7 expression and function in dividing and non-dividing cells from the same tissue and species and to study its role in liver development. Gene disruption and over-expression techniques and channel mutant constructs will be used to complement electrophysiological and molecular approaches to identify the molecular events linking TRPM7 expression, localization and activity to embryonic expansion, unregulated proliferation and terminal differentiation. Four aims are described providing the basis for 5-6 graduate theses and numerous undergraduate projects.