Upregulation of Na+,Cl(-)-coupled betaine/γ-amino-butyric acid transporter BGT1 by Tau tubulin kinase 2.
OBJECTIVE
The serine/threonine kinase Tau-tubulin-kinase 2 (TTBK2) is expressed in various tissues including kidney, liver and brain. Loss of function mutations of TTBK2 lead to autosomal dominant spinocerebellar ataxia type 11 (SCA11). Cell survival is fostered by cellular accumulation of organic osmolytes. Carriers accomplishing cellular accumulation of organic osmolytes include the Na(+), Cl(-)-coupled betaine/γ-amino-butyric acid transporter BGT1. The present study explored whether TTBK2 participates in the regulation of BGT1 activity.


METHODS
Electrogenic transport of GABA was determined in Xenopus oocytes expressing BGT1 with or without wild-type TTBK2, truncated TTBK2[1-450] or kinase inactive mutants TTBK2- KD and TTBK2[1-450]-KD.


RESULTS
Coexpression of wild-type TTBK2, but not of TTBK2[1-450], TTBK2-KD or TTBK2[1-450]-KD, increased electrogenic GABA transport. Wildtype TTBK2 increased the maximal transport rate without significantly modifying affinity of the carrier. Coexpression of wild-type TTBK2 significantly delayed the decline of transport following inhibition of carrier insertion with brefeldin A, indicating that wild-type TTBK2 increased carrier stability in the cell membrane.


CONCLUSIONS
Tau-tubulin-kinase 2 TTBK2 is a powerful stimulator of the osmolyte and GABA transporter BGT1.
Department of Physiology, University of Tübingen, Tübingen, Germany.
Ahmad
A
Almilaji
Carlos
C
Munoz
Zohreh
Z
Hosseinzadeh
Florian
F
Lang
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D050485:GABA Plasma Membrane Transport Proteins; D006801:Humans; D009865:Oocytes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012965:Sodium Chloride / Q000737:chemistry*; D015854:Up-Regulation; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D011994:Recombinant Proteins; C072207:betaine plasma membrane transport proteins; D012965:Sodium Chloride; D005680:gamma-Aminobutyric Acid; C095903:tau-tubulin kinase; D017346:Protein Serine-Threonine Kinases