title: Pumilio-2 regulates translation of Nav1.6 to mediate homeostasis of membrane excitability.
abstract: The ability to regulate intrinsic membrane excitability, to maintain consistency of action potential firing, is critical for stable neural circuit activity. Without such mechanisms, Hebbian-based synaptic plasticity could push circuits toward activity saturation or, alternatively, quiescence. Although now well documented, the underlying molecular components of these homeostatic mechanisms remain poorly understood. Recent work in the fruit fly, Drosophila melanogaster, has identified Pumilio (Pum), a translational repressor, as an essential component of one such mechanism. In response to changing synaptic excitation, Pum regulates the translation of the voltage-gated sodium conductance, leading to a concomitant adjustment in action potential firing. Although similar homeostatic mechanisms are operational in mammalian neurons, it is unknown whether Pum is similarly involved. In this study, we report that Pum2 is indeed central to the homeostatic mechanism regulating membrane excitability in rat visual cortical pyramidal neurons. Using RNA interference, we observed that loss of Pum2 leads to increased sodium current (I(Na)) and action potential firing, mimicking the response by these neurons to being deprived of synaptic depolarization. In contrast, increased synaptic depolarization results in increased Pum2 expression and subsequent reduction in INa and membrane excitability. We further show that Pum2 is able to directly bind the predominant voltage-gated sodium channel transcript (NaV1.6) expressed in these neurons and, through doing so, regulates translation of this key determinant of membrane excitability. Together, our results show that Pum2 forms part of a homeostatic mechanism that matches membrane excitability to synaptic depolarization in mammalian neurons.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Driscoll
authors.forename: Nara I
authors.initials: NI
authors.lastname: Muraro
authors.forename: Miaomiao
authors.initials: M
authors.lastname: He
authors.forename: Richard A
authors.initials: RA
authors.lastname: Baines
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002462:Cell Membrane / Q000502:physiology*; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D008297:Male; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D014176:Protein Biosynthesis / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology; D016601:RNA-Binding Proteins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014793:Visual Cortex / Q000502:physiology
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; C539713:PUM2 protein, rat; D016601:RNA-Binding Proteins; C507811:Scn8a protein, rat