The Drosophila small conductance potassium channel (SK) negatively regulates nociception

Abstract

SummaryInhibition of nociceptor activity is important for the prevention of spontaneous pain and hyperalgesia. To identify the critical K + channels that regulate nociceptor excitability we performed a forward genetic screen using a Drosophila larval nociception paradigm.Knockdown of three K + channel loci, the small conductance calcium-activated potassium channel (SK), seizure and tiwaz, resulted in marked hypersensitive nociception behaviors.In more detailed studies of SK, we found that hypersensitive phenotypes could be recapitulated with a genetically null allele. Importantly, the null mutant phenotype could be rescued with tissue specific expression of an SK cDNA in nociceptors. Optical recordings from nociceptive neurons showed a significant increase in mechanically activated Ca 2+ signals in SK mutant nociceptors. SK showed expression in peripheral neurons. Interestingly SK proteins localized to axons of these neurons but were not detected in dendrites. Our findings suggest a major role for SK channels in the regulation of nociceptor excitation and they are inconsistent with the hypothesis that the important site of action is within dendrites.

Gαq and Phospholipase Cβ signaling regulate nociceptor sensitivity in Drosophila melanogaster larvae

“…With this in mind, it is important to note that PIP2 affects the activity of many types of ion channels (for review see Hille et al, 2015 ). PIP2 hydrolysis by NorpA may regulate the function of any number of ion channels that control nociceptor sensitivity, including voltage-gated calcium channels and small-conductance potassium channels ( Neely et al, 2010 ; Walcott et al, 2017 ). We also cannot rule out that the generation of IP3 and DAG second messengers by PIP2 hydrolysis is the principal mechanism by which NorpA regulates nociceptor sensitivity, as these mechanisms are well known to mediate store-operated calcium release, activation of protein kinases, and regulation of the neurotransmitter release machinery.…”

Peer Review #3 of "Gαq and Phospholipase Cβ signaling regulate nociceptor sensitivity in Drosophila melanogaster larvae (v0.1)"

“…With this in mind, it is important to note that PIP2 effects the activity of many types of ion channels (for review see (Hille et al 2015)). PIP2 hydrolysis by NorpA may regulate the function of any number of ion channels that control nociceptor sensitivity, including voltage-gated calcium channels and small-conductance potassium channels (Neely et al 2010;Walcott et al 2017). We also cannot rule out that the generation of IP3 and DAG second messengers by PIP2 hydrolysis is the principal mechanism by which NorpA regulates nociceptor sensitivity, as these mechanisms are well known to mediate store-operated calcium release, activation of protein kinases, and regulation of the neurotransmitter release machinery.…”