Background K⁺ conductance TASK-channels belong to the family of two-pore-domain potassium (K2P) channels. They are highly involved in regulation of neuronal excitability, cardiovascular homeostasis and endocrine activity. In diverse native systems TASK-channel activity is downregulated by activation of G_q-protein coupled receptors (G_qPCR)(1). For example they are implicated in the cholinergic inhibition of I_K,SO in cerebellar granule neurons, in the Angiotensin II stimulated Aldosterone secretion in adrenal zona-glomerulosa cells and in the vasoconstriction of the pulmonary artery by Endothelin-1 (2).

The mechanism underlying this inhibition has remained elusive. Recently good evidence exists for two competing hypothesis: (i) TASK-channels could be either blocked directly by the Gq-alpha subunit released on G_qPCR activation or (ii) TASK-channel activity could require the phosphoinositide PI(4,5)P2, that is cleaved when Gq-alpha activates Phospholipase C (PLC)(3).

We investigated the role of PLC mediated Phosphoinositide cleavage in the process of TASK-channel regulation by G_qPCRs in the intact cell. By using recently developed genetically encoded switchable phosphatases and interfering with PLC activity, we consistently find that alteration of the PLC substrate PI(4,5)P2 alone is not efficient to inhibit TASKs. However blockage of PLC leads to an abolishment of G_qPCR induced TASK inhibition.

Our results show that the hydrolysis of PI(4,5)P2 does not directly inhibit TASKs. On the other hand we could demonstrate that PLC activation is an essential step for G_qPCR-mediated TASK channel inhibition. Consequently we propose that a regulatory mechanism downstream of PI(4,5)P2-hydrolysis mediates TASK-channel inhibition.

Supported by DFG grants OL240/3-1 (FOR1086) and SFB 593 (TP A12) to D. O.

References: 

1. P. Enyedi, G. Czirjak,Physiol Rev90, 559 (Apr, 2010).

2. D. A. Bayliss, P. Q. Barrett,Trends Pharmacol Sci29, 566 (Nov, 2008).

3. A. Mathie,J Physiol578, 377 (Jan 15, 2007).