A dominant mutation in a neuronal acetylcholine receptor subunit leads to motor neuron degeneration in Caenorhabditis elegans.
Inappropriate or excessive activation of ionotropic receptors can have dramatic consequences for neuronal function and, in many instances, leads to cell death. In Caenorhabditis elegans, nicotinic acetylcholine receptor (nAChR) subunits are highly expressed in a neural circuit that controls movement. Here, we show that heteromeric nAChRs containing the acr-2 subunit are diffusely localized in the processes of excitatory motor neurons and act to modulate motor neuron activity. Excessive signaling through these receptors leads to cell-autonomous degeneration of cholinergic motor neurons and paralysis. C. elegans double mutants lacking calreticulin and calnexin-two genes previously implicated in the cellular events leading to necrotic-like cell death (Xu et al. 2001)-are resistant to nAChR-mediated toxicity and possess normal numbers of motor neuron cell bodies. Nonetheless, excess nAChR activation leads to progressive destabilization of the motor neuron processes and, ultimately, paralysis in these animals. Our results provide new evidence that chronic activation of ionotropic receptors can have devastating degenerative effects in neurons and reveal that ion channel-mediated toxicity may have distinct consequences in neuronal cell bodies and processes.
Barbagallo
Belinda
B
Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Prescott
Hilary A
HA
Boyle
Patrick
P
Climer
Jason
J
Francis
Michael M
MM
D019943:Amino Acid Substitution; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D017173:Caenorhabditis elegans / Q000235:genetics*; D037281:Calnexin / Q000235:genetics; D037282:Calreticulin / Q000235:genetics; D016923:Cell Death; D017930:Genes, Reporter; D006706:Homeostasis / Q000502:physiology; D007473:Ion Channels / Q000502:physiology; D008124:Locomotion / Q000235:genetics / Q000502:physiology; D018613:Microscopy, Confocal; D016472:Motor Neuron Disease / Q000235:genetics* / Q000473:pathology; D009336:Necrosis; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D010243:Paralysis / Q000235:genetics / Q000473:pathology; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D037282:Calreticulin; D007473:Ion Channels; D011978:Receptors, Nicotinic; D037281:Calnexin