Neumann Joachim, Boknik Peter, Kirchhefer Uwe, Gergs Ulrich
Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Str. 4, D-06097 Halle, Germany.
Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Westfälische Wilhelms-Universität, Domagkstraße 12, D-48149 Münster, Germany.
Cell Signal. 2021 Sep;85:110035. doi: 10.1016/j.cellsig.2021.110035. Epub 2021 May 6.
Protein phosphatases are important, for example, as functional antagonists of β-adrenergic stimulation of the mammalian heart. While β-adrenergic stimulations increase the phosphorylation state of regulatory proteins and therefore force of contraction in the heart, these phosphorylations are reversed and thus force is reduced by the activity of protein phosphatases. In this context the role of PP5 and PP2C is starting to unravel. They do not belong to the same family of phosphatases with regard to sequence homology, many similarities with regard to location, activation by lipids and putative substrates have been worked out over the years. We also suggest which pathways for regulation of PP5 and/or PP2C described in other tissues and not yet in the heart might be useful to look for in cardiac tissue. Both phosphatases might play a role in signal transduction of sarcolemmal receptors in the heart. Expression of PP5 and PP2C can be increased by extracellular stimuli in the heart. Because PP5 is overexpressed in failing animal and human hearts, and because overexpression of PP5 or PP2C leads to cardiac hypertrophy and KO of PP5 leads to cardiac hypotrophy, one might argue for a role of PP5 and PP2C in heart failure. Because PP5 and PP2C can reduce, at least in vitro, the phosphorylation state of proteins thought to be relevant for cardiac arrhythmias, a role of these phosphatases for cardiac arrhythmias is also probable. Thus, PP5 and PP2C might be druggable targets to treat important cardiac diseases like heart failure, cardiac hypertrophy and cardiac arrhythmias.
例如，蛋白磷酸酶作为哺乳动物心脏β-肾上腺素能刺激的功能拮抗剂具有重要意义。虽然β-肾上腺素能刺激会增加调节蛋白的磷酸化状态，从而增强心脏的收缩力，但这些磷酸化会被逆转，因此蛋白磷酸酶的活性会降低心脏的收缩力。在这种情况下，PP5和PP2C的作用开始逐渐明晰。就序列同源性而言，它们不属于同一磷酸酶家族，但多年来已经发现了它们在定位、脂质激活和假定底物方面的许多相似之处。我们还指出，在其他组织而非心脏中描述的尚未在心脏中研究的PP5和/或PP2C的调控途径，可能值得在心脏组织中探索。这两种磷酸酶可能在心脏肌膜受体的信号转导中发挥作用。心脏中的细胞外刺激可增加PP5和PP2C的表达。由于PP5在衰竭的动物和人类心脏中过度表达，并且由于PP5或PP2C的过度表达会导致心脏肥大，而PP5基因敲除会导致心脏萎缩，因此有人认为PP5和PP2C在心力衰竭中发挥作用。由于PP5和PP2C至少在体外可以降低被认为与心律失常相关的蛋白质的磷酸化状态，因此这些磷酸酶在心律失常中也可能发挥作用。因此，PP5和PP2C可能是治疗心力衰竭、心脏肥大和心律失常等重要心脏疾病的可药物作用靶点。
