Transcriptional up-regulation of cell surface NaV1.7 sodium channels by insulin-like growth factor-1 via inhibition of glycogen synthase kinase-3β in adrenal chromaffin cells: enhancement of 22Na+ influx, 45Ca2+ influx and catecholamine secretion
ABSTRACT Insulin-like growth factor-1 (IGF-1) plays important roles in the regulation of neuronal development. The electrical activity of Na(+) channels is crucial for the regulation of synaptic formation and maintenance/repair of neuronal circuits. Here, we examined the effects of chronic IGF-1 treatment on cell surface expression and function of Na(+) channels. In cultured bovine adrenal chromaffin cells expressing Na(V)1.7 isoform of voltage-dependent Na(+) channels, chronic IGF-1 treatment increased cell surface [(3)H]saxitoxin binding by 31%, without altering the Kd value. In cells treated with IGF-1, veratridine-induced (22)Na(+) influx, and subsequent (45)Ca(2+) influx and catecholamine secretion were augmented by 35%, 33%, 31%, respectively. Pharmacological properties of Na(+) channels characterized by neurotoxins were similar between nontreated and IGF-1-treated cells. IGF-1-induced up-regulation of [(3)H]saxitoxin binding was prevented by phosphatydil inositol-3 kinase inhibitors (LY204002 or wortmannin), or Akt inhibitor (Akt inhibitor IV). Glycogen synthase kinase-3 (GSK-3) inhibitors (LiCl, valproic acid, SB216763 or SB415286) also increased cell surface [(3)H]saxitoxin binding by ∼ 33%, whereas simultaneous treatment of IGF-1 with GSK-3 inhibitors did not produce additive increasing effect on [(3)H]saxitoxin binding. IGF-1 (100 nM) increased Ser(437)-phosphorylated Akt and Ser(9)-phosphorylated GSK-3β, and inhibited GSK-3β activity. Treatment with IGF-1, LiCl or SB216763 increased protein level of Na(+) channel α-subunit; it was prevented by cycloheximide. Either treatment increased α-subunit mRNA level by ∼ 48% and accelerated α-subunit gene transcription by ∼ 30% without altering α-subunit mRNA stability. Thus, inhibition of GSK-3β caused by IGF-1 up-regulates cell surface expression of functional Na(+) channels via acceleration of α-subunit gene transcription.
- Nature Reviews Genetics 03/2012; 13(4):225. DOI:10.1038/nrg3201 · 39.79 Impact Factor
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ABSTRACT: Central and peripheral insulin-like peptides (ILPs), which include insulin, insulin-like growth factor 1 (IGF1) and IGF2, exert many effects in the brain. Through their actions on brain growth and differentiation, ILPs contribute to building circuitries that subserve metabolic and behavioural adaptation to internal and external cues of energy availability. In the adult brain each ILP has distinct effects, but together their actions ultimately regulate energy homeostasis - they affect nutrient sensing and regulate neuronal plasticity to modulate adaptive behaviours involved in food seeking, including high-level cognitive operations such as spatial memory. In essence, the multifaceted activity of ILPs in the brain may be viewed as a system organization involved in the control of energy allocation.Nature Reviews Neuroscience 04/2012; 13(4):225-39. DOI:10.1038/nrn3209 · 31.38 Impact Factor
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ABSTRACT: Endothelin-1 and voltage-dependent sodium channels are involved in control and suppression of neuropathological factors, which contribute to sculpting the neuronal network. We previously demonstrated that veratridine-induced NaV1.7 sodium channel activation caused intracellular calcium elevation, catecholamine secretion and tau dephosphorylation in adrenal chromaffin cells. The aim of this study was to examine whether endothelin-1 could modulate NaV1.7. Our results indicated that endothelin-1 decreased the protein level of NaV1.7 and the veratridine-induced increase in intracellular calcium. In addition, it also abolished the veratridine-induced dephosphorylation of tau and the phosphorylation of glycogen synthase kinase-3β and extracellular signal-regulated kinase. These findings suggest that the endothelin-1-induced down-regulation of NaV1.7 diminishes NaV1.7-related catecholamine secretion and dephosphorylation of tau.FEBS letters 02/2013; 587(7). DOI:10.1016/j.febslet.2013.02.013 · 3.34 Impact Factor