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Vol. 289, Issue 1, 188-193, April 1999
Institut für Pharmakologie und Toxikologie, Universität
Münster, Münster, Germany (J.N., P.B.);
Abteilung
Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf,
Hamburg, Germany (R.M., H.S., N.Z.); and
Department of Medicine and
Krannert Institute of Cardiology, Indiana University School of
Medicine, Indianapolis, Indiana (L.R.J.)
-Adrenoceptor stimulation acts in the heart in part by increasing
the phosphorylation state of phospholamban and phospholemman. There is
evidence that the -adrenoceptor-mediated increase in phospholamban
phosphorylation is in part due to inhibition of type 1 phosphatases.
The aim of the present study was to elucidate which phosphatases
dephosphorylate phospholamban and phospholemman in the human heart. In
the past, cardiac serine/threonine phosphatases have been studied using
phosphorylase a as substrate. Here, type 1 and type 2A
phosphatase activities were studied in preparations from failing human
hearts using phosphorylated phospholamban and phospholemman as
substrates. Phospholamban and phospholemman phosphatase activity was
detectable in human cardiac homogenates. Moreover, using a
heparin-Sepharose column, the catalytic subunits of type 1 and type 2A
phosphatases could be separated from human ventricles. Okadaic acid and
cantharidin inhibited phosphatase activities dephosphorylating
phospholamban, phospholemman, and phosphorylase a in
homogenates in a concentration-dependent manner. However, okadaic acid
was more potent. Cantharidin inhibited type 2A and type 1 activities
against all substrates studied with IC50 values <15 nM and
>290 nM, respectively. Okadaic acid inhibited type 1 and type 2A
phosphatase activities as effectively but 10-30 times more potently
than cantharidin. This work provides evidence that in the human heart,
type 1 and 2A phosphatases are involved in the dephosphorylation of
phospholamban and phospholemman and could play a role in the effects of
-adrenergic stimulation in the heart.
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