Cell Excitability Necessary for Male Mating Behavior inCaenorhabditis elegansIs Coordinated by Interactions Between Big Current and Ether-A-Go-Go Family K+ Channels

Abstract

Variations in K + channel composition allow for differences in cell excitability and, at an organismal level, provide flexibility to behavioral regulation. When the function of a K + channel is disrupted, the remaining K + channels might incompletely compensate, manifesting as abnormal organismal behavior. In this study, we explored how different K + channels interact to regulate the neuromuscular circuitry used by Caenorhabditis elegans males to protract their copulatory spicules from their tail and insert them into the hermaphrodite's vulva during mating. We determined that the big current K + channel (BK)/SLO-1 genetically interacts with ether-a-gogo (EAG)/EGL-2 and EAG-related gene/UNC-103 K + channels to control spicule protraction. Through rescue experiments, we show that specific slo-1 isoforms affect spicule protraction. Gene expression studies show that slo-1 and egl-2 expression can be upregulated in a calcium/calmodulin-dependent protein kinase II-dependent manner to compensate for the loss of unc-103 and conversely, unc-103 can partially compensate for the loss of SLO-1 function. In conclusion, an interaction between BK and EAG family K + channels produces the muscle excitability levels that regulate the timing of spicule protraction and the success of male mating behavior.

Ether-à-go-go family voltage-gated K+ channels evolved in an ancestral metazoan and functionally diversified in a cnidarian–bilaterian ancestor

“…However, Erg channels also activate at sub-threshold potentials and could therefore play a role in the regulation of sub-threshold excitability. Some Erg channels have lost inactivation but retained sub-threshold activation (Martinson et al, 2014), and the channels have been implicated in the regulation of excitation threshold in Caenorhabditis, Drosophila and mouse (Collins and Koelle, 2013;Hardman and Forsythe, 2009;Hirdes et al, 2009;LeBoeuf and Garcia, 2012;Titus et al, 1997). Sub-threshold activation seems to be a unifying functional feature of all EAG family channels that have been functionally expressed.…”

“…Drosophila motor neurons (Srinivasan et al, 2012) and neuromuscular excitability in C. elegans (LeBoeuf and Garcia, 2012). Both mammalian Eag orthologs have been genetically associated with neuronal excitability control (Ufartes et al, 2013;Yang et al, 2013), but the cellular mechanisms have not been explored.…”

“…Similarly, pharmacologic block of Erg (Eag-related gene) channels enhances the excitability of neurons in several brain regions (Hardman and Forsythe, 2009;Hirdes et al, 2009;Hirdes et al, 2005;Ji et al, 2012;Niculescu et al, 2013). A role for Eag and Erg channels in the regulation of neuromuscular excitation appears conserved in Drosophila and Caenorhabditis elegans (Collins and Koelle, 2013;Garcia and Sternberg, 2003;LeBoeuf and Garcia, 2012;Srinivasan et al, 2012;Titus et al, 1997), but the function of Elk (Eag-like K + channel) has not yet been examined in invertebrate model systems.…”

“…We have previously expressed Nematostella (sea anemone) Erg channel paralogs and demonstrated that an inactivating I Kr -like phenotype of Ether-à-go-go family voltage-gated K + channels evolved in an ancestral metazoan and functionally diversified in a cnidarianbilaterian ancestor mammalian Erg channels is the likely functional phenotype of Erg channels in the cnidarian-bilaterian ancestor (Martinson et al, 2014). Erg channels are specialized for delayed repolarization of broad action potentials and/or regulation of excitation threshold (Garcia and Sternberg, 2003;LeBoeuf and Garcia, 2012;Martinson et al, 2014;Sanguinetti and Tristani-Firouzi, 2006;Titus et al, 1997). Mammalian Erg1 plays a critical role in the repolarization of cardiac action potential plateaus and loss-of-function mutations in humans are a significant cause of long QT syndrome, which is characterized by delayed repolarization of cardiac action potential (Sanguinetti and Tristani-Firouzi, 2006).…”

Functional evolution of Erg potassium channel gating reveals an ancient origin for I Kr

“…Temperature-sensitive mutations in the seizure locus that encodes DmErg cause bursts of uncoordinated motor output (19) suggestive of changes in subthreshold excitability. The Caenorhabditis elegans Erg ortholog (CeErg, encoded by unc-103) has not been functionally expressed, but genetic analysis demonstrates that it regulates the excitation threshold of vulva muscles in females and protractor muscles in males (20)(21)(22)(23).…”