Tyrosine Phosphorylation Modulates Current Amplitude and Kinetics of a Neuronal Voltage-Gated Potassium Channel

Fadool, James M.; Holmes, Todd C.; Berman, Kevin; Dagan, Daniel; Levitan, Irwin B.

doi:10.1152/jn.1997.78.3.1563

Cited by 95 publications

(112 citation statements)

References 45 publications

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“…Without the assisting role of the amino terminus in CMD action, stabilization of opening does not occur, and P o is lowered by Src phosphorylation. Precedent for dual tyrosine phosphorylation of K ϩ channels involved in tyrosine kinase modulation comes from Kv1.3 channels, which are doubly phosphorylated by v-Src at a tyrosine in each terminus of the channel, for which a kinase-dead v-Src mutant has little effect (1,7). In that study, adapter proteins were shown to act as controllers of Src action either facilitating or blocking the signal.…”

Section: Discussionmentioning

confidence: 98%

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Dual Phosphorylations Underlie Modulation of Unitary KCNQ K+ Channels by Src Tyrosine Kinase

Li¹,

Langlais

Gamper³

et al. 2004

Journal of Biological Chemistry

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Src tyrosine kinase suppresses KCNQ (M-type) K ؉ channels in a subunit-specific manner representing a mode of modulation distinct from that involving G protein-coupled receptors. We probed the molecular and biophysical mechanisms of this modulation using mutagenesis, biochemistry, and both whole-cell and single channel modes of patch clamp recording. Immunoprecipitation assays showed that Src associates with KCNQ2-5 subunits but phosphorylates only KCNQ3-5. Using KCNQ3 as a background, we found that mutation of a tyrosine in the amino terminus (Tyr-67) or one in the carboxyl terminus (Tyr-349) abolished Src-dependent modulation of heterologously expressed KCNQ2/3 heteromultimers. The tyrosine phosphorylation was much weaker for either the KCNQ3-Y67F or KCNQ3-Y349F mutants and wholly absent in the KCNQ3-Y67F/Y349F double mutant. Biotinylation assays showed that Src activity does not alter the membrane abundance of channels in the plasma membrane. In recordings from cell-attached patches containing a single KCNQ2/3 channel, we found that Src inhibits the open probability of the channels. Kinetic analysis was consistent with the channels having two discrete open times and three closed times. Src activity reduced the durations of the longest open time and lengthened the longest closed time of the channels. The implications for the mechanisms of channel regulation by the dual phosphorylations on both channel termini are discussed.Regulation of neuronal activity by tyrosine kinases has emerged as an important theme in neurobiology. In addition to their well documented role in neuronal proliferation and trophic responses are actions on several different types of ion channels that link alterations in electrical activity to neuronal plasticity. Examples are non-receptor tyrosine kinase modulation of Shaker family K ϩ channels (1-7) and growth factor receptor regulation of voltage-gated Ca 2ϩ channels (8 -10). The family of KCNQ genes make K ϩ channels composed of KCNQ1-5 subunits, which are responsible for M-type K ϩ currents in the nervous and auditory systems (11-14) and slow delayed rectifier K ϩ currents in the heart (15, 16). KCNQ1-5 channels have recently been incorporated into the Kv nomenclature as Kv7.1-5 (17). Compared with other Kv channels, KCNQ channels have an extended intracellular carboxyl terminus that seems to be the target of many modulatory signals. Examples are modulation by Ca 2ϩ (18), using calmodulin as the channel Ca 2ϩ sensor (19), and regulation by plasma membrane phosphoinositides (20 -22) perhaps in concert with protein kinase C (23).Src is the prototypical member of the family of non-receptor tyrosine kinases that also includes Fyn, Hck, Lck, and Yes. These proteins often act via two mechanisms: by binding to substrate via Src homology (SH) 1 2 and SH3 domains and/or by phosphorylation of target tyrosines (24). For example, distinct effects of Src actions by these two mechanisms have been described for Kv1.4 and Kv1.5 K ϩ channels (6). We recently showed subunit-specific modulation of KCNQ c...

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Section: Discussionmentioning

confidence: 98%

“…These proteins often act via two mechanisms: by binding to substrate via Src homology (SH) 1 2 and SH3 domains and/or by phosphorylation of target tyrosines (24). For example, distinct effects of Src actions by these two mechanisms have been described for Kv1.4 and Kv1.5 K ϩ channels (6).…”

mentioning

confidence: 99%

Dual Phosphorylations Underlie Modulation of Unitary KCNQ K+ Channels by Src Tyrosine Kinase

Li¹,

Langlais

Gamper³

et al. 2004

Journal of Biological Chemistry

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“…Both receptor and cellular tyrosine kinases, have been shown to acutely suppress Kv1.3 current by direct tyrosine phosphorylation. [3][4][5][6][7][8] Moreover, tyrosine kinase-mediated suppression of Kv1.3 current can be further modulated by direct proteinprotein interactions by adaptor and scaffolding proteins such as postsynaptic density-95 (PSD-95), n-Shc or Grb10. 9,10 Kv1.3 is involved in a variety of functions and is expressed in both excitable and nonexcitable tissues including, but not limited to, the olfactory bulb, 11 white and brown adipose tissue, 12 skeletal muscle, 12 the hypothalamus, 13 T lymphocytes 14 and their mitochondria, 15 and brain microglia.…”

Section: Introductionmentioning

confidence: 99%

Kv1.3 gene-targeted deletion alters longevity and reduces adiposity by increasing locomotion and metabolism in melanocortin-4 receptor-null mice

2008

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Objective: Gene-targeted deletion of the voltage-gated potassium channel, Kv1.3, results in 'super-smeller' mice that have altered firing patterns of mitral cells in the olfactory bulb, modified axonal targeting to glomerular synaptic units, and behaviorally have an increased ability to detect and discriminate odors. Moreover, the Kv1.3-null mice weighed less than their wild-type counterparts, have modified ingestive behaviors, and are resistant to fat deposition following a moderately high-fat dietary regime. In this study, we investigate whether or not gene-targeted deletion of Kv1.3 (Shaker family member) can abrogate weight gain in a genetic model of obesity, the melanocortin-4 receptor-null mouse (MC4R-null). Design: Mice with double gene-targeted deletions of Kv1.3 and MC4R were generated by interbreeding Kv1.3 (Kv)-and MC4R-null mouse lines to homozygosity. Developmental weights, nose to anus length, fat pad weight, fasting serum chemistry, oxygen consumption, carbon dioxide respiration, locomotor activity and caloric intake were monitored in control, Kv-null, MC4R-null and Kv/MC4R-null mice. Physiological and metabolic profiles were acquired at postnatal day 60 (P60) in order to explore changes linked to body weight at the reported onset of obesity in the MC4R-null model. Results: Gene-targeted deletion of Kv1.3 in MC4R-null mice reduces body weight by decreasing fat deposition and subsequent fasting leptin levels, without changing the overall growth, fasting blood glucose or serum insulin. Gene-targeted deletion of Kv1.3 in MC4R-null mice significantly extended lifespan and increased reproductive success. Basal or light-phase mass-specific metabolic rate and locomotor activity were not affected by genetic deletion of Kv1.3 in MC4R-null mice but darkphase locomotor activity and mass-specific metabolism were significantly increased resulting in increased total energy expenditure. Conclusions: Gene-targeted deletion of Kv1.3 can reduce adiposity and total body weight in a genetic model of obesity by increasing both locomotor activity and mass-specific metabolism.

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“…One of the major functions of SFKs is to regulate the activity of voltage-gated ion channels (Cataldi et al, 1996;Fadool et al, 1997) and ionotropic neuro-transmitter receptors (Moss et al, 1995;Wan et al, 1997;Wang et al, 2004). Src was also found to be involved in synaptic transmission and plasticity as well as excitotoxicity since Src regulated NMDA receptor activity (Wang and Salter, 1994;Yu et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Brevetoxin-induced phosphorylation of Pyk2 and Src in murine neocortical neurons involves distinct signaling pathways

et al. 2007

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Brevetoxins (PbTx-1 to PbTx-10) are potent lipid soluble polyether neurotoxins produced by the marine dinoflagellate Karenia brevis. Brevetoxins bind to site 5 of the α-subunit of voltage-gated sodium channels (VGSCs) and augment Na + influx. In neocortical neurons brevetoxins elevate intracellular Ca 2+ and augment NMDA receptor signaling. In this study, we explored the effects of PbTx-2 on Pyk2 and Src activation in neocortical neurons. We found that both Pyk2 and Src were activated following PbTx-2 exposure. PbTx-2-induced Pyk2 Tyr402 phosphorylation was dependent on elevation of Ca 2+ influx through NMDA receptors. Moreover, Pyk2 Tyr402 phosphorylation was also found to require PKC activation inasmuch as RO-31-8425 and GF 109203x both attenuated the response. In contrast, PbTx-2-induced Src Tyr416 phosphorylation involved a Gq-coupled receptor inasmuch as U73122, a specific PLC inhibitor, abolished the response. This Gq-coupled receptor appears to be mGluR 5. The PKCδ inhibitor rottlerin abolished PbTx-2-induced Src activation demonstrating that this isoform of PKC is involved in the activation of Src by PbTx-2. Considered together these data suggest that although activation of neuronal Pyk2 and Src result from PbTx-2 stimulation of VGSC, engagement of these two non-receptor tyrosine kinases involves distinct signaling pathways.

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Tyrosine Phosphorylation Modulates Current Amplitude and Kinetics of a Neuronal Voltage-Gated Potassium Channel

Cited by 95 publications

References 45 publications

Dual Phosphorylations Underlie Modulation of Unitary KCNQ K+ Channels by Src Tyrosine Kinase

Dual Phosphorylations Underlie Modulation of Unitary KCNQ K+ Channels by Src Tyrosine Kinase

Kv1.3 gene-targeted deletion alters longevity and reduces adiposity by increasing locomotion and metabolism in melanocortin-4 receptor-null mice

Brevetoxin-induced phosphorylation of Pyk2 and Src in murine neocortical neurons involves distinct signaling pathways

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