The mono-ADP-ribosyltransferase ARTD10 regulates the voltage-gated K + channel Kv1.1 through protein kinase C delta
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RESEARCH ARTICLE
Open Access
The mono-ADP-ribosyltransferase ARTD10 regulates the voltage-gated K+ channel Kv1.1 through protein kinase C delta Yuemin Tian1, Patricia Korn2, Priyanka Tripathi1,3, Daniel Komnig4,5, Dominik Wiemuth1, Azadeh Nikouee1, Arno Classen6, Carsten Bolm6, Björn H. Falkenburger4,5,7, Bernhard Lüscher2 and Stefan Gründer1*
Abstract Background: ADP-ribosylation is a ubiquitous post-translational modification that involves both mono- and polyADP-ribosylation. ARTD10, also known as PARP10, mediates mono-ADP-ribosylation (MARylation) of substrate proteins. A previous screen identified protein kinase C delta (PKCδ) as a potential ARTD10 substrate, among several other kinases. The voltage-gated K+ channel Kv1.1 constitutes one of the dominant Kv channels in neurons of the central nervous system and the inactivation properties of Kv1.1 are modulated by PKC. In this study, we addressed the role of ARTD10-PKCδ as a regulator of Kv1.1. Results: We found that ARTD10 inhibited PKCδ, which increased Kv1.1 current amplitude and the proportion of the inactivating current component in HeLa cells, indicating that ARTD10 regulates Kv1.1 in living cells. An inhibitor of ARTD10, OUL35, significantly decreased peak amplitude together with the proportion of the inactivating current component of Kv1.1-containing channels in primary hippocampal neurons, demonstrating that the ARTD10-PKCδ signaling cascade regulates native Kv1.1. Moreover, we show that the pharmacological blockade of ARTD10 increases excitability of hippocampal neurons. Conclusions: Our results, for the first time, suggest that MARylation by ARTD10 controls neuronal excitability. Keywords: Ion channel, Potassium channel, ADP ribosylation, Posttranslational modification, ADP ribosyltransferase, Protein kinase C delta, PARP10
Background ADP-ribosyltransferases (ARTs) regulate many cellular processes including DNA damage repair and transcriptional regulation by post-translational modification of their target proteins with ADP-ribose groups [1]. Diphtheria toxin-like ADP-ribosyltransferases are classified as ARTDs [2]. While ARTD1, also named PARP1 and the founding member of the PARP family, transfers iteratively several ADP-ribose groups to its target proteins in * Correspondence: [email protected] 1 Institute of Physiology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany Full list of author information is available at the end of the article
a process termed poly-ADP-ribosylation (or PARylation) [3], several other ARTDs, including ARTD10, transfer only a single ADP-ribose group onto their target proteins (mono-ADP-ribosylation or MARylation) [4]. MARylation is a widely used posttranslational modification; however, only few cellular substrates have been identified and the functional consequences are ill defined. ARTD10 was initially described as an interaction partner of the nuclear oncoprotein MYC [5]. ARTD10 MARylates itself and core histones [4]. It shuttles between the nucleus and the cytosol, but resides mainly in the cytosol
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