Abstract
Nicotinic acetylcholine receptors (nAChR) are present in many excitable tissues and are found both pre and post-synaptically. Through their non-specific cationic permeability, these nAChRs have excitatory roles in neurotransmission, neuromodulation, synaptic plasticity, and neuroprotection. Thus, nAChR mislocalization or functional deficits are associated with many neurological disease states. Therefore identifying the mechanisms that regulate nAChR expression and function will inform our understanding of normal as well as pathological physiological conditions and offer avenues for potential therapeutic advances. Taking advantage of the genetic tractability of the soil nematode Caenorhabditis elegans, a forward genetic screen was performed to isolate regulators of the vertebrate α7 nAChR homologue ACR-16. From this screen a novel regulator of the ACR-16 receptor was identified, the sarco(endo)plasmic reticulum calcium ATPase sca-1. The sca-1 mutant affects ACR-16 receptor level at the NMJ, receptor functionality, and synaptic transmission. Responses to pressure-ejected nicotine in sca-1 mutants are indistinguishable from wild type, which implies the ACR-16 receptors are mislocalized at the NMJ. Changes in cytosolic baseline calcium levels in sca-1 and other mutants indicates a calcium-driven regulation mechanism of the α7-like NAChR ACR-16.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 104-115 |
| Number of pages | 12 |
| Journal | Cell Calcium |
| Volume | 72 |
| DOIs | |
| State | Published - Jun 2018 |
| Externally published | Yes |
Bibliographical note
Funding Information:We thank Andrew Raduski for assistance with analysis of the whole genome sequencing data and Simon Alford for use of his lab’s calcium imaging equipment. The UNC-29:RFP worm line was provided by the lab of Jean-Louis Bessereau, the UNC-49:GFP worm line was provided by the lab of Bruce Bamber, and the zx1659 worm line was provided by the lab of Alexander Gottschalk. Marc Hammarlund provided plasmids used in the construction of the SCA-1:mCherry rescuing construct. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440 ). Strains were also obtained from the National Bioresource Project. We thank Jean-Louis Bessereau for comments on the manuscript.
Publisher Copyright:
© 2018 Elsevier Ltd
Keywords
- C. elegans
- Electrophysiology
- Neuromuscular junction (NMJ)
- Nicotinic acetylcholine receptors (nAChRs)
- Sarco(endo)plasmic reticulum calcium ATPase (SERCA)
- Synaptic transmission