Phosphorylation-dependent Regulation of Kv2.1 Channel Activity at Tyrosine 124 by Src and by Protein-tyrosine Phosphatase ε

Tiran, Zohar; Peretz, Asher; Attali, Bernard; Elson, Ari

doi:10.1074/jbc.m212766200

Cited by 57 publications

(67 citation statements)

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“…The authors suggested that the difference compared with results of K v 2.1 in a heterologous expression system could be due to the interaction of K v 2.1 with silent K v subunits or to a different phosphorylation state of K v 2.1 in cultured neurons compared with heterologous expression. The degree of phosphorylation influences the voltage dependent properties of K v 2.1, and different degrees of K v 2.1 phosphorylation have been reported in different cells (15,17,18,21,35). To exclude the hypothesis that differentially phosphorylated K v 2.1 channels caused the two components of the inactivation curve, we investigated the effect of dephosphorylation.…”

Section: Discussionmentioning

confidence: 99%

K_v2.1 and silent K_v subunits underlie the delayed rectifier K⁺ current in cultured small mouse DRG neurons

Bocksteins¹,

Raes²,

Vijver³

et al. 2009

American Journal of Physiology-Cell Physiology

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Silent voltage-gated K+ (Kv) subunits interact with Kv2 subunits and primarily modulate the voltage dependence of inactivation of these heterotetrameric channels. Both Kv2 and silent Kv subunits are expressed in the mammalian nervous system, but little is known about their expression and function in sensory neurons. This study reports the presence of Kv2.1, Kv2.2, and silent subunit Kv6.1, Kv8.1, Kv9.1, Kv9.2, and Kv9.3 mRNA in mouse dorsal root ganglia (DRG). Immunocytochemistry confirmed the protein expression of Kv2.x and Kv9.x subunits in cultured small DRG neurons. To investigate if Kv2 and silent Kv subunits are underlying the delayed rectifier K+ current ( IK) in these neurons, Kv2-mediated currents were isolated by the extracellular application of rStromatoxin-1 (ScTx) or by the intracellular application of Kv2 antibodies. Both ScTx- and anti-Kv2.1-sensitive currents displayed two components in their voltage dependence of inactivation. Together, both components accounted for approximately two-thirds of IK. A comparison with results obtained in heterologous expression systems suggests that one component reflects homotetrameric Kv2.1 channels, whereas the other component represents heterotetrameric Kv2.1/silent Kv channels. These observations support a physiological role for silent Kv subunits in small DRG neurons.

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Section: Discussionmentioning

confidence: 99%

K_v2.1 and silent K_v subunits underlie the delayed rectifier K⁺ current in cultured small mouse DRG neurons

Bocksteins¹,

Raes²,

Vijver³

et al. 2009

American Journal of Physiology-Cell Physiology

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“…cyt-PTPe dephosphorylates Kv2.1 predominantly at Y124, thereby down-regulating channel activity and countering phosphorylation of this residue by c-Src. RPTPe can dephosphorylate Kv2.1 as well (Peretz et al, 2000;Tiran et al, 2003). We, therefore, expressed Kv2.1 in the presence of Y527F Src, which cannot be activated by RPTPe, to ensure channel phosphorylation.…”

Section: Neu Activates C-src Via Rptpe Phosphorylation D Berman-golanmentioning

confidence: 99%

Neu-mediated phosphorylation of protein tyrosine phosphatase epsilon is critical for activation of Src in mammary tumor cells

Berman-Golan

Elson

2007

Oncogene

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The receptor-type protein tyrosine phosphatase epsilon (RPTPe) activates c-Src in mammary tumor cells induced in vivo by Neu. Tumor cells lacking RPTPe exhibit reduced c-Src activity, appear less transformed morphologically and proliferate slower in vitro and in vivo. Expression of Src rescues most of these phenotypes, indicating that c-Src activity is important for maintaining the transformed phenotype. However, the molecular mechanisms that control activation of c-Src by RPTPe are unknown. We show that Neu induces phosphorylation of RPTPe exclusively at its C-terminal Y695, and that this phosphorylation is required for activation of c-Src by RPTPe. Phosphorylation of RPTPe does not affect its activity toward another substrate, the voltage-gated potassium channel Kv2.1, suggesting that phosphorylation directs RPTPe activity toward c-Src. Phosphorylation of RPTPe reduces its dimerization at the cell membrane, although this does not affect its activity significantly. RPTPe is subject to strong auto-and trans-dephosphorylation, suggesting that dephosphorylation limits the activation of c-Src downstream of Neu. We conclude that an Neu-RPTPe-Src signaling pathway exists in mammary tumor cells, in which phosphorylation of RPTPe by Neu directs RPTPe to activate c-Src. Reversible phosphorylation of RPTPe at Y695 may thus function as a 'molecular switch', which affects the substrate specificity of the phosphatase.

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“…It has been established that this type of regulation involves the production of cAMP and subsequent phosphorylation by protein kinase A (PKA). Tyrosine kinases have also been reported to modulate the activity of cardiac ion channels (Shuba & McDonald, 1997;Zhou et al, 1997;Wang & Lipsius, 1998;Hool et al, 1998;Maier et al, 1999;Mason et al, 2002;Tiran et al, 2003). We previously demonstrated that genistein, a tyrosine kinase inhibitor, can increase the sensitivity of cardiac ion channels to b 1 -AR stimulation, suggesting that basal tyrosine kinase activity inhibits badrenergic responsiveness in cardiac myocytes (Hool et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Redox modulation of basal and β‐adrenergically stimulated cardiac L‐type Ca²⁺ channel activity by phenylarsine oxide

Sims

Harvey

2004

British J Pharmacology

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1 Phenylarsine oxide (PAO) is commonly used to inhibit tyrosine phosphatase activity. However, PAO can affect a variety of different processes because of its ability to promote sulfhydryl oxidation. In the present study, we investigated the effects that PAO has on basal and b-adrenergically stimulated L-type Ca 2 þ channel activity in isolated cardiac myocytes. 2 Extracellular application of PAO transiently stimulated the basal L-type Ca 2 þ channel activity, whereas it irreversibly inhibited protein kinase A (PKA)-dependent regulation of channel activity by isoproterenol, forskolin and 8-CPT-cAMP (8-p-chlorophenylthioadenosine 3 0 ,5 0 -cyclic monophosphate). PAO also inhibited channel activity irreversibly stimulated in the presence of adenosine 5 0 -(3-thiotriphosphate) tetralithium salt. 3 Neither the stimulatory nor the inhibitory effects of PAO were affected by the tyrosine kinase inhibitor lavendustin A, suggesting that tyrosine phosphorylation is not involved. 4 Extracellular application of the sulfhydryl-reducing agent dithiothreitol (DTT) antagonized both the stimulatory and inhibitory effects of PAO. Yet, following intracellular dialysis with DTT, only the inhibitory effect of PAO was antagonized. 5 The inhibitory effect of PAO was mimicked by intracellular, but not extracellular application of the membrane impermeant thiol oxidant 5,5 0 -dithio-bis(2-nitrobenzoic acid).6 These results suggest that the stimulatory effect of PAO results from oxidation of sulfhydryl residues at an extracelluar site and the inhibitory effect is due to redox regulation of an intracellular site that affects the response of the channel to PKA-dependent phosphorylation. It is concluded that the redox state of the cell may play a critical role in modulating b-adrenergic responsiveness of the Ltype Ca 2 þ channel in cardiac myocytes.

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Phosphorylation-dependent Regulation of Kv2.1 Channel Activity at Tyrosine 124 by Src and by Protein-tyrosine Phosphatase ε

Cited by 57 publications

References 50 publications

K_v2.1 and silent K_v subunits underlie the delayed rectifier K⁺ current in cultured small mouse DRG neurons

K_v2.1 and silent K_v subunits underlie the delayed rectifier K⁺ current in cultured small mouse DRG neurons

Neu-mediated phosphorylation of protein tyrosine phosphatase epsilon is critical for activation of Src in mammary tumor cells

Redox modulation of basal and β‐adrenergically stimulated cardiac L‐type Ca²⁺ channel activity by phenylarsine oxide

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Phosphorylation-dependent Regulation of Kv2.1 Channel Activity at Tyrosine 124 by Src and by Protein-tyrosine Phosphatase ε

Cited by 57 publications

References 50 publications

Kv2.1 and silent Kv subunits underlie the delayed rectifier K+ current in cultured small mouse DRG neurons

Kv2.1 and silent Kv subunits underlie the delayed rectifier K+ current in cultured small mouse DRG neurons

Neu-mediated phosphorylation of protein tyrosine phosphatase epsilon is critical for activation of Src in mammary tumor cells

Redox modulation of basal and β‐adrenergically stimulated cardiac L‐type Ca2+ channel activity by phenylarsine oxide

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K_v2.1 and silent K_v subunits underlie the delayed rectifier K⁺ current in cultured small mouse DRG neurons

K_v2.1 and silent K_v subunits underlie the delayed rectifier K⁺ current in cultured small mouse DRG neurons

Redox modulation of basal and β‐adrenergically stimulated cardiac L‐type Ca²⁺ channel activity by phenylarsine oxide