Caenorhabditis ElegansJunctophilin has Tissue-Specific Functions and Regulates Neurotransmission with Extended-Synaptotagmin

The junctophilin family of proteins tether together plasma membrane (PM) and endoplasmic reticulum (ER) membranes, and couple PM- and ER-localized calcium channels. Understandingin vivofunctions of junctophilins is of great interest for dissecting the physiological roles of ER-PM contact sites. Here, we show that the soleC. elegansjunctophilin JPH-1 localizes to discrete membrane contact sites in neurons and muscles and has important tissue-specific functions.jph-1null mutants display slow growth and development due to weaker contraction of pharyngeal muscles, leading to reduced feeding. In the body wall muscle, JPH-1 co-localizes with the PM-localized EGL-19 voltage-gated calcium channel and ER-localized UNC-68/RyR calcium channel, and is required for animal movement. We also find an unexpected cell non-autonomous effect ofjph-1in axon regrowth after injury. In neurons, JPH-1 co-localizes with the membrane contact site protein Extended-SYnaptoTagmin 2 (ESYT-2) and modulates neurotransmission. Interestingly,jph-1andesyt-2null mutants display mutual suppression in their response to aldicarb, suggesting that JPH-1 and ESYT-1 have antagonistic roles in neuromuscular synaptic transmission. Our genetic double mutant analysis also reveals thatjph-1functions in overlapping pathways with two PM-localized voltage-gated calcium channels,egl-19andunc-2,andunc-68/RyRfor animal health and development. Finally, we show thatunc-68/RyRis required for JPH-1 localization to ER-PM puncta. Our data demonstrate important roles for junctophilin in cellular physiology, and also provide insights into how junctophilin functions together with other calcium channelsin vivo.