Membrane potential-regulated transcription of the resting K+ conductance TASK-3 via the calcineurin pathway.
The 2P domain K(+) channel TASK-3 is highly expressed in cerebellar granule neurons where it has been proposed to underlie the K(+) leak conductance, IKso. In a previous work we showed that expression of TASK-3 increases in cerebellar granule neurons as they mature in culture. Here we show that within the cerebellum, levels of TASK-3 mRNA increase as granule neurons migrate to their adult positions and receive excitatory mossy fiber input. To understand the mechanism of this increase in TASK-3 expression we used an in vitro model culturing the neurons in either depolarizing conditions mimicking neuronal activity (25K, 25 mm KCl) or in conditions which approach deafferentation (5K, 5 mm KCl). An important increase in TASK-3 mRNA is uniquely observed in 25K and is specific since other background K(+) channel levels remain unchanged or decrease. The rise in TASK-3 mRNA leads to an increase in TASK-3 protein and the IKso conductance resulting in hyperpolarization. Blocking L-type calcium channels or their downstream effector calcineurin, abrogates TASK-3 expression and IKso, leading to hyperexcitability. This is the first study demonstrating that depolarization-induced Ca(2+) entry can directly regulate cellular excitability by dynamically regulating the transcription of a resting K(+) conductance. The appearance of this conductance may play an important role in the transition of depolarized immature neurons to their mature hyperpolarized state during neuronal development.
Zanzouri
Marc
M
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR 6097, Université de Nice-Sophia Antipolis, Valbonne 06560, France.
Lauritzen
Inger
I
Duprat
Fabrice
F
Mazzuca
Michel
M
Lesage
Florian
F
Lazdunski
Michel
M
Patel
Amanda
A
D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D019556:COS Cells; D019703:Calcineurin / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002522:Chlorocebus aethiops; D008564:Membrane Potentials; D009474:Neurons / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D020746:Calcium Channels, L-Type; C407082:Kcnk9 protein, rat; D024683:Potassium Channels, Tandem Pore Domain; D012333:RNA, Messenger; D019703:Calcineurin; D011188:Potassium