TGF-β1 Enhances Kv2.1 Potassium Channel Protein Expression and Promotes Maturation of Cerebellar Granule Neurons

Members of the transforming growth factor-beta (TGF-beta) family of cytokines are involved in diverse physiological processes. Although TGF-beta is known to play multiple roles in the mammalian central nervous system (CNS), its role in neuronal development has not been explored. We have studied the effects of TGF-beta 1 on the electrophysiological properties and maturation of rat primary cerebellar granule neurons (CGNs). We report that incubation with TGF-beta 1 increased delayed rectifier potassium current (I-K) amplitudes in a dose-and time-dependent manner, but did not affect the kinetic properties of the channel. Exposure to TGF-beta 1 (20 ng/ml) for 36 h led to a 37.2% increase in I-K amplitudes. There was no significant change in mRNA levels for the key Kv2.1 channel protein, but translation blockade abolished the increase in protein levels and channel activity, arguing that TGF-beta 1 increases I-K amplitudes by upregulating translation of the Kv2.1 channel protein. Although TGF-beta 1 treatment did not affect the activity of protein kinase A (PKA), and constitutive activation of PKA with forskolin failed to increase I-K amplitudes, inhibition of PKA prevented channel upregulation, demonstrating that basal PKA activity is required for TGF-beta 1 stimulation of I-K channel activity. TGF-beta 1 also promoted the expression of the gamma-aminobutyric acid (GABA(A)) receptor alpha 6 subunit, a marker of mature CGNs, and calcium influx during depolarizing stimuli was reduced by TGF-beta 1. The effects of TGF-beta 1 were only observed during a narrow developmental time-window, and were lost as CGNs matured. These findings suggest that TGF-beta 1 upregulates K+ channel expression and I-K currents and thereby promotes CGN maturation. J. Cell. Physiol. 227: 297-307, 2012. (C) 2011 Wiley Periodicals, Inc.