The Ste20 Kinases Ste20-related Proline-Alanine-rich Kinase and Oxidative-stress Response 1 Regulate NKCC1 Function in Sensory Neurons

Yang, Geng; Höke, Ahmet; Delpire, Eric

doi:10.1074/jbc.m900142200

Cited by 68 publications

(87 citation statements)

References 29 publications

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“…The transport activity of NKCC1 depends on the phosphorylation of four threonine residues in its N terminus , and Thr-208 in rat NKCC1). The kinases that mediate NKCC1 phosphorylation are SPAK and OSR1, both members of the germinal center kinase (GCK)-VI subfamily (9,12,(36)(37)(38). Both kinases are regulated by the WNK family of protein kinases (10).…”

Section: Discussionmentioning

confidence: 99%

Molecular components of signal amplification in olfactory sensory cilia

Hengl

Kaneko

Dauner

et al. 2010

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

100

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The mammalian olfactory system detects an unlimited variety of odorants with a limited set of odorant receptors. To cope with the complexity of the odor world, each odorant receptor must detect many different odorants. The demand for low odor selectivity creates problems for the transduction process: the initial transduction step, the synthesis of the second messenger cAMP, operates with low efficiency, mainly because odorants bind only briefly to their receptors. Sensory cilia of olfactory receptor neurons have developed an unusual solution to this problem. They accumulate chloride ions at rest and discharge a chloride current upon odor detection. This chloride current amplifies the receptor potential and promotes electrical excitation. We have studied this amplification process by examining identity, subcellular localization, and regulation of its molecular components. We found that the Na + /K + /2Cl − cotransporter NKCC1 is expressed in the ciliary membrane, where it mediates chloride accumulation into the ciliary lumen. Gene silencing experiments revealed that the activity of this transporter depends on the kinases SPAK and OSR1, which are enriched in the cilia together with their own activating kinases, WNK1 and WNK4. A second Cl − transporter, the Cl − /HCO 3 − exchanger SLC4A1, is expressed in the cilia and may support Cl − accumulation. The calcium-dependent chloride channel TMEM16B (ANO2) provides a ciliary pathway for the excitatory chloride current. These findings describe a specific set of ciliary proteins involved in anion-based signal amplification. They provide a molecular concept for the unique strategy that allows olfactory sensory neurons to operate as efficient transducers of weak sensory stimuli.chloride | olfaction | sensory transduction | transport | kinase M ammalian olfactory receptor neurons (ORNs) present to the air a tuft of sensory cilia equipped with odorant receptors. Upon contact with odorants, these receptors actuate a transduction cascade that leads to firing of action potentials. This cascade has an unusual, two-stage organization (1). First, the activated odorant receptors induce a rise of the second messengers cAMP and Ca 2+ in the cilia, a process that involves cAMP-gated, Ca 2+ -permeable ion channels. In the second stage, inflowing Ca 2+ opens Cl − channels. By conducting a depolarizing Cl − efflux from the cilia, these channels amplify the receptor potential approximately 10-fold, thus helping to excite the neuron even when stimulation is weak. ORNs accumulate chloride through the Na + /K + /2Cl − cotransporter NKCC1 and maintain an elevated intracellular Cl − concentration (2, 3) to support amplification. Accordingly, gene ablation of NKCC1, as well as the pharmacologic suppression of Cl − accumulation or Cl − efflux, strongly inhibits the sensory response of ORNs (3-5). Although these observations provide a robust concept for signal amplification, several points are still unclear. These concern both the Cl − accumulation process and the excitatory Cl − currents. First, ...

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Section: Discussionmentioning

confidence: 99%

Molecular components of signal amplification in olfactory sensory cilia

Hengl

Kaneko

Dauner

et al. 2010

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

100

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“…The generation of SPAK knock-out (KO, SPAK Ϫ/Ϫ ) mice has been described in detail previously (11,24). Briefly, the SPAK gene (Stk39) was disrupted by duplicating exon 6 and inserting tyrosinase (Tyr), neomycin resistance (neo), and 50 hypoxanthine phosphoribosyltransferase (hprt) genes between the two exons.…”

Section: Methodsmentioning

confidence: 99%

“…To begin to understand why salt reabsorption in the distal convoluted tubule might be so profoundly dependent on SPAK, compared with the thick ascending limb, we first sought to settle a puzzling phenotype issue between different SPAK null mice (7,11,24). One strain of mice, generated and studied by Yang et al (7), exhibit frank hypotension, volume contraction, and hyperaldosteronism, whereas the other strain, generated by Delpire and Gagnon (11,24) and as studied by McCormick et al (3) do not exhibit hypotension or hypoaldosteronism.…”

Section: Decompensated Gitelman Phenotype In Young Spak Null Micementioning

confidence: 99%

SPAK Isoforms and OSR1 Regulate Sodium-Chloride Co-transporters in a Nephron-specific Manner

Grimm

Taneja

Liu

et al. 2012

Journal of Biological Chemistry

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119

159

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Background: Full-length SPAK is thought to be necessary and sufficient to activate NCC in the distal convoluted tubule (DCT). Results: SPAK knock-out disrupts a signaling network, involving OSR1, in the DCT but not the TAL, preventing NCC activation. Conclusion: SPAK and OSR1 function interdependently in the DCT to positively regulate NCC. Significance: This study provides insights into the mechanisms whereby SPAK/OSR1 regulates renal salt transport.

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“…In a peripheral nerve injury model, an increase in [Cl Ϫ ] i among regenerating sensory neurons accelerates growth rate of neurites, suggesting that chloride homeostasis plays a major role in nerve repair (Pieraut et al, 2007). In peripheral neurons, transcriptional modifications, phosphorylation and protein trafficking have been identified as cellular mechanisms responsible for upregulation or downregulation of [Cl Ϫ ] i (Morales-Aza et al, 2004;Galan and Cervero, 2005;Pieraut et al, 2007;Geng et al, 2009). Consistent with the role of cation-Cl Ϫ cotransporters in pain processing, inflammatory mediators such nerve growth factor, bradykinin or prostaglandin all induce accumulation of chloride (Nakajima et al, 2007;Funk et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

Pieraut¹,

Lucas²,

Sangari³

et al. 2011

J. Neurosci.

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The cation-chloride cotransporter NKCC1 plays a fundamental role in the central and peripheral nervous systems by setting the value of intracellular chloride concentration. Following peripheral nerve injury, NKCC1 phosphorylation-induced chloride accumulation contributes to neurite regrowth of sensory neurons. However, the molecules and signaling pathways that regulate NKCC1 activity remain to be identified. Functional analysis of cotransporter activity revealed that inhibition of endogenously produced cytokine interleukin-6 (IL-6), with anti-mouse IL-6 antibody or in IL-6 Ϫ/Ϫ mice, prevented chloride accumulation in a subset of axotomized neurons. Nerve injury upregulated the transcript and protein levels of IL-6 receptor in myelinated, TrkB-positive sensory neurons of murine lumbar dorsal root ganglia. Expression of phospho-NKCC1 was observed mainly in sensory neurons expressing IL-6 receptor and was absent from IL-6 Ϫ/Ϫ dorsal root ganglia. The use of IL-6 receptor blocking-function antibody or soluble IL-6 receptor, together with pharmacological inhibition of Janus kinase, confirmed the role of neuronal IL-6 signaling in chloride accumulation and neurite growth of a subset of axotomized sensory neurons. Cell-specific expression of interleukin-6 receptor under pathophysiological conditions is therefore a cellular response by which IL-6 contributes to nerve regeneration through neuronal NKCC1 phosphorylation and chloride accumulation.

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The Ste20 Kinases Ste20-related Proline-Alanine-rich Kinase and Oxidative-stress Response 1 Regulate NKCC1 Function in Sensory Neurons

Cited by 68 publications

References 29 publications

Molecular components of signal amplification in olfactory sensory cilia

Molecular components of signal amplification in olfactory sensory cilia

SPAK Isoforms and OSR1 Regulate Sodium-Chloride Co-transporters in a Nephron-specific Manner

An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

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