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Growth Factor Receptor Tyrosine Kinases Acutely Regulate Neuronal Sodium Channels Through the Src Signaling Pathway

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Growth Factor Receptor Tyrosine Kinases Acutely Regulate Neuronal Sodium Channels Through the Src Signaling Pathway The Journal of Neuroscience, January 15, 1998, 18(2):590–600 Growth Factor Receptor Tyrosine Kinases Acutely Regulate Neuronal Sodium Channels through the Src Signaling Pathway Michael D. Hilborn,1 Richard R. Vaillancourt,2 and Stanley G. Rane1 1Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, and 2Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721 Growth factor receptor tyrosine kinase (RTK)-activated signal- abrogate sodium channel inhibition in response to NGF and ing pathways are well established regulators of neuronal growth PDGF, respectively, showing that the intrinsic RTK activity of and development, but whether these signals provide mecha- these receptors is necessary for sodium channel inhibition. Use nisms for acute modulation of neuronal activity is just beginning of PDGF receptor mutants deficient for specific signaling activ- to be addressed. We show in pheochromocytoma (PC12) cells ities demonstrated that this inhibition is dependent on RTK that acute application of ligands for both endogenous RTKs interaction with Src but not with other RTK-associated signaling [trkA, basic FGF (bFGF) receptor, and epidermal growth factor molecules. Inhibition was also compromised in cells expressing (EGF) receptor] and ectopically expressed platelet-derived dominant-negative Ras. These results suggest a possible growth factor (PDGF) receptors rapidly inhibits whole-cell so- mechanism for acute physiological actions of RTKs, and they dium channel currents, coincident with a hyperpolarizing shift in indicate regulatory functions for Ras and Src that may comple- the voltage dependence of inactivation. Sodium channel inhi- ment the roles of these signaling proteins in long-term neuronal bition by trkA and PDGF receptors is mutually occlusive, sug- regulation. gestive of a common signal transduction mechanism. Further- Key words: PC12 cells; sodium channels; growth factor re- more, specific inhibitors for trkA and PDGF RTK activities ceptor tyrosine kinases; PDGF receptors; NGF; Ras; Src Growth factors constitute a family of polypeptides essential for growth factors can modulate synaptic activity in hippocampal the establishment and maintenance of the mature nervous sys- neurons and developing Xenopus neuromuscular junctions (Ter- tem. Expressed throughout the CNS and PNS, growth factors act lau and Seifert, 1989; Abe et al., 1991; Kang and Schuman, 1995), by binding to their cognate receptor tyrosine kinases (RTKs), as well as modulate short-term potentiation and LTP (Lohof et which autophosphorylate and subsequently activate a complex of al., 1993; Stoop and Poo, 1996). These studies suggest that ion signaling proteins including the well characterized Ras and channel modulation may be an important component of acute mitogen-activated kinase (MAPK) pathway, phosphatidylinositol growth factor actions, and they are complemented by work show- 3-kinase (PI3-K), phospholipase Cg (PLCg), and the Src family of ing growth factors can acutely modulate the high-voltage- 1 1 1 nonreceptor tyrosine kinases (for review, see Panayotou and activated Ca 2 channel and Ca 2 -activated K channels (Wil- Waterfield, 1993; Johnson and Vaillancourt, 1994; Kaplan and dering et al., 1995; Holm et al., 1997). However, the signaling Stephens, 1994; Szebere´nyi and Erhardt, 1994; van der Geer et paths underlying these physiological events are undetermined, 1 al., 1994). The variety of neuronal responses to growth factors, and although both NMDA receptors and the human Kv1.5 K including proliferation and migration, establishment and mainte- channel associate with the nonreceptor tyrosine kinase Src nance of synaptic connections, and survival of many mature (Holmes et al., 1996; Yu et al., 1997), it is not yet known whether neurons, ultimately depends on the activation of specific compo- this interaction underlies a growth factor-initiated action. Fur- nents comprising this signaling network (for review, see Korsch- thermore, studies suggesting that the activation of the MAPK ing, 1993; Snider, 1994; van der Geer et al., 1994; Bothwell, 1995; cascade is essential for events associated with long-term facilita- Lewin and Barde, 1996). tion in Aplysia neurons have not ascertained whether growth In addition to the wealth of information on long-term cellular factors are vital in initiating this response (Bailey et al., 1997; effects, there is increasing evidence that growth factors and their Martin et al., 1997). Thus, there is much to be determined signaling pathways play pivotal roles in the acute regulation of the concerning how growth factors physiologically modulate the ma- mature nervous system (for review, see Thoenen, 1995). In hip- ture nervous system and which signaling pathways are essential to pocampal neurons, depolarizing stimuli and stimulation protocols this modulation. that induce long-term potentiation (LTP) increase neurotrophin Past efforts to examine the signaling mechanisms that medi- mRNA levels (Lu et al., 1991; Patterson et al., 1992). In turn, ate the effects of chronic growth factor exposure in both the PNS and CNS have used the well characterized rat pheochro- Received Aug. 28, 1997; revised Oct. 23, 1997; accepted Oct. 24, 1997. mocytoma (PC12) model neuronal cell line (for review, see This work was supported by a grant from the Whitehall Foundation (S.G.R.), Grant DK 08897 (R.R.V.), and a Predoctoral Fellowship from the American Heart Chao, 1992; Keegan and Halegoua, 1993; Marshall, 1995). Association, Indiana Affiliate (M.D.H.). We are grateful to Dr. S. Rossie for critical Application of NGF causes PC12 cells to differentiate into a review of this manuscript. neuronal-like phenotype characterized by numerous morpho- Correspondence should be addressed to Dr. Stanley G. Rane, Department of Biological Sciences, Lilly Hall, West Lafayette, IN 47907. logical and physiological changes, including the persistent ac- Copyright © 1998 Society for Neuroscience 0270-6474/98/180590-11$05.00/0 tivation of the Ras and MAPK pathway, cessation of cellular Hilborn et al. • Growth Factor RTK Regulation of Neuronal Na1 Channels J. Neurosci., January 15, 1998, 18(2):590–600 591 1 division, neurite extension, the induction of immediate early HEPES, pH 7.3. For recording voltage-gated Ca 2 channel currents, the and neuronal-specific genes, and an induction of electrical bath solution consisted of 135 mM TEA-Cl, 4 mM KCl, 10 mM BaCl2 ,1 mM MgCl ,5mM glucose, 10 mM HEPES, and 1 mM tetrodotoxin, pH excitability because of an increase in ion channel expression 2 7.3. In all cases, the patch pipette solution was 150 mM CsCl, 2 mM (Greene and Tischler, 1982). Via the analysis of PC12 cell lines MgATP, 0.5 mM GTP, 2 mM BAPTA, and 10 mM HEPES, pH 7.3. expressing mutant receptors or intracellular signaling mole- Whole-cell capacitive transients, elicited by 20 mV depolarizing steps, cules, the signaling mechanisms that mediate these long-term were compensated with the analog compensation circuitry of the patch- changes have been well characterized (Rausch et al., 1990; clamp amplifier. Whole-cell capacitance, a measure of membrane area, was read directly from the compensation control dial of the amplifier. Szebere´nyi et al., 1990; Ginty et al., 1992; Traverse et al., 1992; We waited from 2 to 5 min after establishing whole-cell patch-clamp Fanger et al., 1993, 1997; Cavalie´ et al., 1994; Cowley et al., access before beginning experimental data collection. During this time, 1 1994; Loeb et al., 1994; Stephens et al., 1994; Vaillancourt et the Na I–V relationship was assessed by holding the cell at 290 mV and 2 al., 1995; Pollock and Rane, 1996; Hilborn et al., 1997). For by evoking command steps from 60 to 60 mV in 10 mV increments at 1.5–3 sec intervals. Two changes were observed when this protocol was example, analyses of PC12 cell lines expressing mutated repetitively administered. First, as has been noted in a number of studies 1 platelet-derived growth factor (PDGF) receptors deficient for on voltage-gated currents, the Na I–V relationship shifted to the left by activating specific signaling pathways have determined that 5–10 mV during the first 30–90 sec of recording. We also observed that both Src and PLCg are required for growth factor-induced in addition to this shift, current amplitudes increased at any given voltage during the first 1–3 min of recording, and then they stabilized. Growth neurite extension (Vaillancourt et al., 1995). An analysis of 1 factor inhibition of Na current was assessed at the command voltage these same cell lines, along with PC12 cells expressing the N17 giving maximal current (as shown by the I–V protocol) only after these 1 Ras dominant-negative mutant, demonstrated that although spontaneous changes in Na current were complete. Any cell that 1 growth factor-induced upregulation of brain type II/IIA Na showed continuous variations in current of .5% at this voltage was rejected. To test for significant differences in growth factor inhibition of channels is independent of Ras activation, the activation of Src 1 Na current between experimental groups, we used a two-tailed, non- is important for establishing the full functional expression of paired, t test (at p , 0.05). All experiments were performed at 22–25°C. these channels (Fanger et al., 1993, 1997; Pollock and Rane, Growth factor and drug application. Growth factors dissolved in the 1996). bath solution were acutely applied to cells via pressure ejection from In this report, we use this
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