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MiRP1 Modulates HCN2 Channel Expression and Gating in Cardiac Myocytes
Ist Teil von
The Journal of biological chemistry, 2004-10, Vol.279 (42), p.43497-43502
Ort / Verlag
United States: American Society for Biochemistry and Molecular Biology
Erscheinungsjahr
2004
Quelle
MEDLINE
Beschreibungen/Notizen
MinK-related protein (MiRP1 or KCNE2) interacts with the hyperpolarization-activated, cyclic nucleotidegated (HCN) family
of pacemaker channels to alter channel gating in heterologous expression systems. Given the high expression levels of MiRP1
and HCN subunits in the cardiac sinoatrial node and the contribution of pacemaker channel function to impulse initiation in
that tissue, such an interaction could be of considerable physiological significance. However, the functional evidence for
MiRP1/HCN interactions in heterologous expression studies has been accompanied by inconsistencies between studies in terms
of the specific effects on channel function. To evaluate the effect of MiRP1 on HCN expression and function in a physiological
context, we used an adenovirus approach to overexpress a hemagglutinin (HA)-tagged MiRP1 (HAMiRP1) and HCN2 in neonatal rat
ventricular myocytes, a cell type that expresses both MiRP1 and HCN2 message at low levels. HA-MiRP1 co-expression with HCN2
resulted in a 4-fold increase in maximal conductance of pacemaker currents compared with HCN2 expression alone. HCN2 activation
and deactivation kinetics also changed, being significantly more rapid for voltages between â60 and â95 mV when HA-MiRP1 was
co-expressed with HCN2. However, the voltage dependence of activation was not affected. Co-immunoprecipitation experiments
demonstrated that expressed HA-MiRP1 and HCN2, as well as endogenous MiRP1 and HCN2, co-assemble in ventricular myocytes.
The results indicate that MiRP1 acts as a β subunit for HCN2 pacemaker channel subunits and alters channel gating at physiologically
relevant voltages in cardiac cells.