Abstract
Two pore domain potassium (K2P) channels (KCNKx.x) cause K+leak currents and are major contributors to resting membrane potential. Their roles in dorsal root ganglion (DRG) neurons normally, and in pathological pain models, are poorly understood. Therefore, we examined mRNA levels for 10 K2P channels in L4 and L5 rat DRGs normally, and 1day and 4days after unilateral cutaneous inflammation, induced by intradermal complete Freund's adjuvant (CFA) injections. Spontaneous foot lifting (SFL) duration (spontaneous pain behaviour) was measured in 1day and 4day rats <1h before DRG harvest. mRNA levels for KCNK channels and Kv1.4 relative to GAPDH (n=4–6 rats/group) were determined with real-time RT-PCR. This study is the first to demonstrate expression of THIK1, THIK2 and TWIK2 mRNA in DRGs. Abundance in normal DRGs was, in descending order:Kv1.4>TRESK(KCNK18)>TRAAK(KCNK4)>TREK2(KCNK10)=TWIK2(KCNK6)>TREK1 (KCNK2)=THIK2(KCNK12)>TASK1(KCNK3)>TASK2(KCNK5)>THIK1(KCNK13)=TASK3(KCNK9).During inflammation, the main differences from normal in DRG mRNA levels were bilateral, suggesting systemic regulation, although some channels showed evidence of ipsilateral modulation. By 1day, bilateral K2P mRNA levels had decreased (THIK1) or increased (TASK1, THIK2) but by 4days they were consistently decreased (TASK2, TASK3) or tended to decrease (excluding TRAAK). The decreased TASK2 mRNA was mirrored by decreased protein (TASK2-immunoreactivity) at 4days. Ipsilateral mRNA levels at 4days compared with 1day were lower (TRESK, TASK1, TASK3, TASK2 and THIK2) or higher (THIK1). Ipsilateral SFL duration during inflammation was positively correlated with ipsilateral TASK1 and TASK3 mRNAs, and contralateral TASK1, TRESK and TASK2 mRNAs. Thus changes in K2P mRNA levels occurred during inflammation and for 4 K2P channels were associated with spontaneous pain behaviour (SFL). K2P channels and their altered expression are therefore associated with inflammation-induced pain.
Highlights
Pain of peripheral origin, both acute and chronic/pathological, results from increased CNS input from primary afferent neurons
Of the K2P channels we examined, the maximum mRNA expression was equivalent to ~0.8% of the total glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA, and the lowest expression (TASK3) was equivalent to about 0.023% of GAPDH, a 34-fold difference in median levels between TRESK and TASK3
We provide evidence for modulation of expression of 6 K2P mRNAs during inflammation, and for correlations between mRNA levels for 4 K2P channels and spontaneous pain behaviour
Summary
Both acute and chronic/pathological, results from increased CNS input from primary afferent neurons. The existence of K+ leak currents (IK) was proposed by Goldman (1943) and Hodgkin and Huxley (1952). The K2P channels are encoded by the K2P (originally KCNK) family of genes; 15 distinct isoforms have been cloned, with only 12 apparently functional (Bayliss and Barrett, 2008). K2Ps are grouped and named in families according to functional properties: TWIK, weak inwards rectifiers; THIK, halothane inhibited; TREK, lipid, stretch and temperature activated; TASK, acid inhibited; TALK, alkaline activated; and TRESK, Ca2+ activated (Bayliss and Barrett, 2008; Bittner et al, 2010; Goldstein et al, 2005). Far from being passive, K2P channels are acutely modulated by ligands or
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