Modifying the Subunit Composition of TASK Channels Alters the Modulation of a Leak Conductance in Cerebellar Granule Neurons

Abstract

Two-pore domain potassium (K 2P ) channel expression is believed to underlie the developmental emergence of a potassium leak conductance [I K(SO) ] in cerebellar granule neurons (CGNs), suggesting that K 2P function is an important determinant of the input conductance and resting membrane potential. To investigate the role that different K 2P channels may play in the regulation of CGN excitability, we generated a mouse lacking TASK-1, a K 2P channel known to have high expression levels in CGNs. In situ hybridization and real-time PCR studies in wild-type and TASK-1 knock-outs (KOs) demonstrated that the expression of other K 2P channels was unaltered in CGNs. TASK-1 knock-out mice were healthy and bred normally but exhibited compromised motor performance consistent with altered cerebellar function. Whole-cell recordings from adult cerebellar slice preparations revealed that the resting excitability of mature CGNs was no different in TASK-1 KO and littermate controls. However, the modulation of I K(SO) by extracellular Zn 2ϩ , ruthenium red, and H ϩ was altered. The I K(SO) recorded from TASK-1 knock-out CGNs was no longer sensitive to alkalization and was blocked by Zn 2ϩ and ruthenium red. These results suggest that a TASK-1-containing channel population has been replaced by a homodimeric TASK-3 population in the TASK-1 knock-out. These data directly demonstrate that TASK-1 channels contribute to the properties of I K(SO) in adult CGNs. However, TASK channel subunit composition does not alter the resting excitability of CGNs but does influence sensitivity to endogenous modulators such as Zn 2ϩ and H ϩ .

TASK Channels Determine pH Sensitivity in Select Respiratory Neurons But Do Not Contribute to Central Respiratory Chemosensitivity

“…units in mouse brain, these results are in good agreement with previous reports on different lines of TASK subunit knock-out mice (Aller et al, 2005;Linden et al, 2006;Brickley et al, 2007), although that group noted a slight decrement in performance of TASK-1 knock-outs on the rotarod (Aller et al, 2005) that our data do not reproduce.…”

“…knock-out mice (Aller et al, 2005;Brickley et al, 2007); in addition, that group reported no change in expression of a broad panel of K 2P channels in their TASK knock-out mouse lines (Aller et al, 2005;Brickley et al, 2007). Homozygous single TASK-1 Ϫ/Ϫ and TASK-3 Ϫ/Ϫ knock-out mice and doubly deleted TASK-1 Ϫ/Ϫ :TASK-3 Ϫ/Ϫ mice (hereafter called TASK Ϫ/Ϫ mice) were viable and presented with no obvious health problems.…”

An unexpected role for TASK-3 potassium channels in network oscillations with implications for sleep mechanisms and anesthetic action

“…In the adult mouse forebrain the TASK-3 gene has much stronger expression than TASK-1. In particular, TASK-3 mRNA is abundant in layers 2 to 6 of the neocortex, CA1 hippocampal pyramidal cells, dentate granule cells, and the septum (38,39); the TASK-3 gene is also expressed in parvalbumin-positive GABAergic interneurons (40) in the hippocampus, some subtypes of which aid the generation of theta oscillations (41,42). The TASK-1 gene, by contrast, is poorly expressed in the mouse hippocampus (38).…”

Glucose Inhibition Persists in Hypothalamic Neurons Lacking Tandem-Pore K+Channels

“…Exon 2 excision in offspring was assessed by PCR using primers flanking this region (P3, 5Ј-TGCGAGCTTCAG-AGAGAGGATG-3Ј and P4, 5Ј-ATGCTCTAATCTCCAGTCTG-3Ј). TASK Ϫ/Ϫ mice were generated by crossing TASK3 Ϫ/Ϫ and TASK1 Ϫ/Ϫ mice (Aller et al, 2005). Resulting TASK3 ϩ/Ϫ TASK1 ϩ/Ϫ animals were further crossed, and double KO progeny (TASK Ϫ/Ϫ ) was identified by analyzing tail DNA.…”

“…This response was not significantly different from that of control or TASK1 Ϫ/Ϫ mice. However, because the absence of TASK3 in KO mice could be compensated by TASK1, we also tested glucosensing in TASK1 Ϫ/Ϫ mice (Aller et al, 2005). We also crossed TASK3 Ϫ/Ϫ and TASK1 Ϫ/Ϫ mice to obtain double TASK KO mice (hereafter termed TASK Ϫ/Ϫ mice).…”