Angela de S. Otero, Ph.D.
Research DescriptionNucleoside diphosphate kinases (NDPK) are members of a family of homologous proteins with key roles in the regulation of normal cell function. Alterations in the expression levels or modifications in the primary structure of NDPKs affect profoundly processes such as growth, development, differentiation and programmed cell death. In atrial myocytes, we have shown that NDPK is involved in the G protein-coupled activation of muscarinic K+ channels, a transmembrane signalling pathway that is essential to the physiological modulation of heart function by the parasympathetic nervous system. However, the molecular mechanisms by which NDPKs participate in this and other processes is unknown. All the NDPK proteins share the ability to transfer phosphate between nucleotides, and it has been proposed that their main role is to regenerate the GTP utilized during G-protein signalling, microtubule assembly, and protein synthesis. However, the phosphotransferase activity of NDPK was found to be dispensable for its function in several processes, including muscarinic K+ channel activation.
Work in our laboratory focuses on understanding the molecular mechanisms by which NDPK contributes to the signal transduction pathways that underlie the integrated response of cardiac cells to neurotransmitters. To do so, we are currently isolating and identifying proteins that interact with NDPK in heart, and also examining the effect of specific mutations on NDPK on channel activation. The experimental approaches utilized range from standard biochemical and imunochemical techniques to electrophysiological studies of native and recombinant channels by patch clamp methods.
Otero, A.S. Transphosphorylation and G protein activation. Biochem. Pharmacol. 39, 1399-1404; 1990.
Yi, X. B.; Sweitzer, N.S.; Otero, A.S. Neutralizing antibodies to nucleoside diphosphate kinase inhibit the enzyme in vitro and in vivo. Evidence for two distinct mechanisms of activation of atrial currents by ATPgS. Biochim. Biophys. Acta, 1310, 334-342 (1996)
Xu, L., Murphy, J. ; Otero, A.S. Participation of Nucleoside diphosphate kinase in muscarinic K channel activation does not involve GTP formation. J. biol. Chem. 271, 21120-21125 (1996)