Regulation of ion channels by protein tyrosine phosphorylation

Davis, Michael J.; Wu, Xin; Nurkiewicz, Timothy R.; Kawasaki, Junya; Gui, Peichun; Hill, Michael A.; Wilson, Emily

doi:10.1152/ajpheart.2001.281.5.h1835

Cited by 143 publications

(106 citation statements)

References 278 publications

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“…Phosphorylation sites identified by metabolic labeling experiments, mutational analysis, and electrophysiology (31) concern a small subset of kinases, such as the serine͞threonine kinases PKA and PKC and a few tyrosine kinases (32)(33)(34). Given that Ͼ500 distinct kinase genes are expressed in mammals (35), our knowledge about phosphorylation within ion channel complexes is very incom- plete.…”

Section: Discussionmentioning

confidence: 99%

Identification by mass spectrometry and functional characterization of two phosphorylation sites of KCNQ2/KCNQ3 channels

Surti

Huang

Jan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Neuronal potassium channel subunits of the KCNQ (Kv7) family underlie M-current (I M), and may also underlie the slow potassium current at the node of Ranvier, I Ks. IM and IKs are outwardly rectifying currents that regulate excitability of neurons and myelinated axons, respectively. Studies of native IM and heterologously expressed Kv7 subunits suggest that, in vivo, KCNQ channels exist within heterogeneous, multicomponent protein complexes. KCNQ channel properties are regulated by protein phosphorylation, protein-protein interactions, and protein-lipid interactions within such complexes. To better understand the regulation of neuronal KCNQ channels, we searched directly for posttranslational modifications on KCNQ2͞KCNQ3 channels in vivo by using mass spectrometry. Here we describe two sites of phosphorylation. One site, specific for KCNQ3, appears functionally silent in electrophysiological assays but is located in a domain previously shown to be important for subunit tetramerization. Mutagenesis and electrophysiological studies of the second site, located in the S4 -S5 intracellular loop of all KCNQ subunits, reveal a mechanism of channel inhibition.KCNQ ͉ M-channel ͉ S4 -S5 loop ͉ potassium channels ͉ neuromodulation K CNQ2͞KCNQ3 heteromeric channels are voltage-gated potassium channels that limit repetitive firing of neurons. They underlie M-current (1), a slow, noninactivating potassium current named for its modulation by muscarinic agonists (2). Some KCNQ2͞KCNQ3 subunits reside in axon initial segments and nodes of Ranvier, where action potentials initiate and propagate (3-5). Thus, potent control over neuronal firing patterns exerted by KCNQ2͞KCNQ3 channels reflects both their functionality and their strategic subcellular positioning.Underscoring this physiological importance, mutations of KCNQ2 and KCNQ3 cause human disorders of neural hyperexcitability, including myokymia (6) and benign familial neonatal convulsions (BFNC) (7-9). Although BFNC is a penetrant, dominantly inherited disorder, some pathogenic mutations reduce channel activity as little as 20% (10). Transgenic mice expressing a dominant-negative KCNQ2 mutation show increased neuronal excitability, hyperactive behavior, and spontaneous epileptic seizures (11).Regulated inhibition of KCNQ channels by metabotropic neurotransmission underlies an important form of plasticity in vertebrate sympathetic and central neurons (12, 13). PIP 2 depletion is the likely mechanism mediating the classic muscarinic inhibition of M-current (14-16), but other mechanisms, including phosphorylation, may contribute to channel modulation by other neurotransmitters (16). Indeed, KCNQ1 and KCNQ2 subunits associate with a variety of kinases and phosphatases via A-kinase anchor proteins (17)(18)(19)(20), and mutational studies implicate KCNQ2͞KCNQ3 phosphorylation sites for channel regulation by protein kinase A (PKA), protein kinase C (PKC), and src tyrosine kinase (10, 19, 21, 22). KCNQ2 and KCNQ3 subunits possess large intracellular domains containing many additiona...

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Section: Discussionmentioning

confidence: 99%

Identification by mass spectrometry and functional characterization of two phosphorylation sites of KCNQ2/KCNQ3 channels

Surti

Huang

Jan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, we postulated that pathways other than the RhoA/Rho-kinase pathway might be involved in Ca 2+ sensitization induced by the phorbol ester. Thus, quercetin at a low concentration might not inhibit Ca 2+ mobilization (Low, 1996;Davis et al, 2001) or the phosphorylation of ERK (Shimizu and Weinstein, 2005), protein kinase C-potentiated inhibitory protein for protein phosphatase type 1 (CPI-17) or integrin-linked kinase (ILK) (Deng et al, 2001;Muranyi et al, 2002). Furthermore, quercetin decreased phosphorylation of MYPT1 at Thr855 induced by thromboxane A 2 or phorbol ester (Fig.…”

Section: Discussionmentioning

confidence: 92%

The Inhibitory Effect of Quercetin on the Agonist-Induced Regulation of Vascular Contractility

Je¹,

Jeong²,

La³

2011

Biomolecules and Therapeutics

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“…To investigate the possible involvement of tyrosine phosphorylation in the action of the TK inhibitors, we looked for antagonism of A23 action by orthovanadate, an established inhibitor of phosphotyrosyl phosphatase (PTP) (Swarup et al, 1982;Davis et al, 2001). Two types of experiments were performed on myocytes with near-physiological distributions of Na þ and Ca 2 þ .…”

Section: Antagonism Of A23 Action By Orthovanadatementioning

confidence: 99%

“…The inhibitors are active on external application, and are typically used at concentrations up to 300 mM, with little effect on the activity of other kinases such as protein kinase A (PKA) and protein kinase C (PKC) (Akiyama et al, 1987;Enright & Booth, 1991;O'Dell et al, 1992). Nevertheless, it is commonly acknowledged that these drugs can have direct effects that are unrelated to their actions on TK (for a review, see Davis et al, 2001). In the case of genistein, the direct effects are believed to include activation of cystic fibrosis transmembrane regulator (CFTR) Cl À channels (French et al, 1997;Weinreich et al, 1997;Zhou et al, 1998) and inhibition of various cation channels (Smirnov & Aaronson, 1995;Paillart et al, 1997;Washizuka et al, 1998;Albert et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Cardiac Na⁺–Ca²⁺ exchanger current induced by tyrphostin tyrosine kinase inhibitors

Missan

McDonald

2004

British J Pharmacology

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1 Tyrosine kinase (TK) inhibitors genistein and tyrphostin A23 (A23) inhibited Ca 2 þ currents in guinea-pig ventricular myocytes investigated under standard whole-cell conditions (K þ -free Tyrode's superfusate; EGTA-buffered (pCa-10.5) Cs þ dialysate). However, the inhibitors (100 mM) also induced membrane currents that reversed between À40 and 0 mV, and the objective of the present study was to characterize these currents.2 Genistein-induced current behaved like Cl À current, and was unaffected by either the addition of divalent cations (0.5 mM Cd 2 þ ; 3 mM Ni 2 þ ) that block the Na þ -Ca 2 þ exchanger (NCX), or the removal of external Na þ and Ca 2 þ . 3 A23-induced current was independent of Cl À driving force, and strongly suppressed by addition of Cd 2 þ and Ni 2 þ , and by removal of either external Na þ or Ca 2 þ . These and other results suggested that A23 activated an NCX current driven by submembrane Na þ and Ca 2 þ concentrations higher than those in the bulk cytoplasm. 4 Improved control of intracellular Na þ and Ca 2 þ concentrations was obtained by suppressing cation influx (10 mM verapamil) and raising dialysate Na þ to 7 mM and dialysate pCa to 7. Under these conditions, stimulation by A23 was described by the Hill equation with EC 50 6874 mM and coefficient 1.1, tyrphostin A25 was as effective as A23, and TK-inactive tyrphostin A1 was ineffective. Phosphotyrosyl phosphatase inhibitor orthovanadate (1 mM) antagonized the action of 100 mM A23. 5 The results suggest that activation of cardiac NCX by A23 is due to inhibition of genisteininsensitive TK.

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Regulation of ion channels by protein tyrosine phosphorylation

Cited by 143 publications

References 278 publications

Identification by mass spectrometry and functional characterization of two phosphorylation sites of KCNQ2/KCNQ3 channels

Identification by mass spectrometry and functional characterization of two phosphorylation sites of KCNQ2/KCNQ3 channels

The Inhibitory Effect of Quercetin on the Agonist-Induced Regulation of Vascular Contractility

Cardiac Na⁺–Ca²⁺ exchanger current induced by tyrphostin tyrosine kinase inhibitors

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Regulation of ion channels by protein tyrosine phosphorylation

Cited by 143 publications

References 278 publications

Identification by mass spectrometry and functional characterization of two phosphorylation sites of KCNQ2/KCNQ3 channels

Identification by mass spectrometry and functional characterization of two phosphorylation sites of KCNQ2/KCNQ3 channels

The Inhibitory Effect of Quercetin on the Agonist-Induced Regulation of Vascular Contractility

Cardiac Na+–Ca2+ exchanger current induced by tyrphostin tyrosine kinase inhibitors

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Cardiac Na⁺–Ca²⁺ exchanger current induced by tyrphostin tyrosine kinase inhibitors