The Caenorhabditis elegans unc-103 gene encodes a potassium channel whose sequence is most similar to the ether-a-go-go related gene (erg) type of K+ channels. We find that the n 500 and e 1597 gain-of-function (gf) mutations in unc-103 cause reduced excitation in most muscles, while loss-of-function (lf) mutations cause mild muscle hyper-excitability. Both gf alleles change the same residue near the cytoplasmic end of S6, consistent with this region regulating channel activation. We also report additional dominant-negative and lf alleles of unc-103 that can antagonize or reduce the function of both gf and wild-type alleles. The unc-103 locus contains 6 promoter regions that express unc-103 in different combinations of body-wall and sex-specific muscles, motor-, inter- and sensory-neurons. Each promoter drives transcripts containing a unique first exon, conferring sequence variability to the N-terminus of the UNC-103 protein, while three splice variants introduce variability into the UNC-103 C-terminus. unc-103(0) hermaphrodites prematurely lay embryos that would normally be retained in the uterus and lay eggs under conditions that inhibit egg-laying behavior. In the egg-laying circuit, unc-103 is expressed in vulval muscles and the HSN neurons from different promoters. Supplying the proper UNC-103 isoform to the vulval muscles is sufficient to restore regulation to egg-laying behavior.

The Caenorhabditis elegans male must integrate various environmental cues to ensure proper execution of mating. One step of male mating, the insertion of the male copulatory spicules into its mate, requires UNC-103 ERG (ether-a-go-go-related gene)-like K ϩ channels. unc-103(lf) alleles cause males to protract their spicules spontaneously in the absence of mating cues. To identify proteins that work with UNC-103, we suppressed unc-103(lf) and isolated lev-11(rg1). LEV-11 (tropomyosin) regulates the spicules directly by controlling the male sex muscles and indirectly by controlling the pharyngeal muscles. lev-11-mediated suppression requires the pharyngeal NSM neurosecretory motor neurons; ablating these neurons in lev-11(rg1); unc-103(lf) males restores spontaneous spicule protraction. Additionally, unc-103-induced spicule protraction can be suppressed by reducing a pharyngeal-specific troponin T. These observations demonstrate that non-genitalia cells involved in feeding also mediate male sexual behaviors.

Food deprivation is known to affect physiology and behavior. Changes that occur could be the result of the organism's monitoring of internal and external nutrient availability. In C. elegans, male mating is dependent on food availability; food-deprived males mate with lower efficiency compared to their well-fed counterparts, suggesting that the mating circuit is repressed in low-food environments. This behavioral response could be mediated by sensory neurons exposed to the environment or by internal metabolic cues. We demonstrated that food-deprivation negatively regulates sex-muscle excitability through the activity of chemosensory neurons and insulin-like signaling. Specifically, we found that the repressive effects of food deprivation on the mating circuit can be partially blocked by placing males on inedible food, E. coli that can be sensed but not eaten. We determined that the olfactory AWC neurons actively suppress sex-muscle excitability in response to food deprivation. In addition, we demonstrated that loss of insulin-like receptor (DAF-2) signaling in the sex muscles blocks the ability of food deprivation to suppress the mating circuit. During low-food conditions, we propose that increased activity by specific olfactory neurons (AWCs) leads to the release of neuroendocrine signals, including insulin-like ligands. Insulin-like receptor signaling in the sex muscles then reduces cell excitability via activation of downstream molecules, including PLC-γ and CaMKII.

Accumulated research has demonstrated the beneficial effects of dietary restriction on extending lifespan and increasing cellular stress resistance. However, reducing nutrient intake has also been shown to direct animal behaviors toward food acquisition. Under food-limiting conditions, behavioral changes suggest that neuronal and muscle activities in circuits that are not involved in nutrient acquisition are down-regulated. These dietary-regulated mechanisms, if understood better, might provide an approach to compensate for defects in molecules that regulate cell excitability. We previously reported that a neuromuscular circuit used in Caenorhabditis elegans male mating behavior is attenuated under food-limiting conditions. During periods between matings, sex-specific muscles that control movements of the male's copulatory spicules are kept inactive by UNC-103 ether-a-go-go–related gene (ERG)–like K+ channels. Deletion of unc-103 causes ∼30%–40% of virgin males to display sex-muscle seizures; however, when food is deprived from males, the incidence of spontaneous muscle contractions drops to 9%–11%. In this work, we used genetics and pharmacology to address the mechanisms that act parallel with UNC-103 to suppress muscle seizures in males that lack ERG-like K+ channel function. We identify calcium/calmodulin-dependent protein kinase II as a regulator that uses different mechanisms in food and nonfood conditions to compensate for reduced ERG-like K+ channel activity. We found that in food-deprived conditions, calcium/calmodulin-dependent protein kinase II acts cell-autonomously with ether-a-go-go K+ channels to inhibit spontaneous muscle contractions. Our work suggests that upregulating mechanisms used by food deprivation can suppress muscle seizures.

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