unc-58 encodes one of the 46 two-pore domain potassium channels (K2Ps) in C. elegans. Close human genetic counterparts of
unc-58 are linked to Birk-Barel syndrome and migraine (Barel et al., Am J Hum Genet. 83(2):193-199, 2008; Lafreniere et al., Nat Med. 16(10):1157-1160, 2010). In C. elegans, a gain-of-function (gf) mutation in
unc-58(
e665) causes the worms to adopt a rigid posture with constant shaking. Our first aim was to investigate poorly studied
unc-58(
e665) phenotypes. Second, we wished to determine if pharmacological screening would reveal drugs that corrected these phenotypes. We classified the defects of the gf mutation in
unc-58(
e665) into four categories: development and aging, locomotion, feeding and egg-laying. We covered seeded plates with drugs, allowed them to dry, added worms and made periodic observations of them. We were able to identify drugs that can correct these deficits. Clozapine, the most effective antipsychotic drug used to treat schizophrenia, corrected the locomotion, egg-laying and feeding defects. Structurally similar antipsychotic loxapine also helped to alleviate the defects of
unc-58(
e665) gf animals. Lithium, the front-line drug used for bipolar disorder, corrected the egg-laying and developmental deficits. Both clozapine and lithium activate the SGK signaling pathway in C. elegans (Weeks et al., J Neurosci Res 89:1658, 2011). However, it did not appear they were acting through SGK signaling. The time-course of the effects of clozapine and lithium suggested phosphorylation might be involved. Therefore, we tested whether Akt signaling mediated the drug actions. Among 10 antipsychotics that activate Akt signaling, only haloperidol corrected the locomotion defect. Loratadine, reported as a K2P blocker, corrected the locomotion defect rapidly, indicating that it directly blocked the channel. However, loratadine was the only K+ channel blocker that corrected the locomotion deficit so far. Moreover, it has been shown that PKA down-regulates activity/expression of K2Ps (Cain et al., Mol Cell Neurosci. 37(1):32-39, 2007). Since our data also indicated phosphorylation, we hypothesized that regulating PKA activity can correct the gf in
unc-58(
e665). We were able to show that increasing cAMP levels rescued the defective
unc-58(
e665) locomotion. We want to investigate further these pathways that may provide new ideas about how to develop drugs aimed at K2Ps for the treatment of tremor, dystonia and other disorders.