A previous study reported that a peptide, sensorin-A, is expressed exclusively in mechanosensory neurons having somata in central ganglia of Aplysia. The present study utilized in situ hybridization, staining by nerve back-fill and soma injection, and electrophysiological methods to characterize the locations, numbers, and functions of sensorin-A-expressing neurons and to define the relationships between soma locations and the locations of peripheral axons and receptive fields. Approximately 1,000 cells express sensorin-A mRNA in young adult animals (10-30 g) and 1,200 cells in larger adults (100-300 g). All of the labeled somata are in the CNS, primarily in the abdominal LE, rLE, RE and RF, pleural VC, cerebral J and K, and buccal S clusters. Expression also occurs in a few sparsely distributed cells in most ganglia. Together, receptive fields of all these mechanosensory clusters cover the entire body surface. Each VC cluster forms a somatotopic map of the ipsilateral body, a "sensory aplunculus." Cells in the pleural and cerebral clusters have partially overlapping sensory fields and synaptic targets. Buccal S cells have receptive fields on the buccal mass and lips and display notable differences in electrophysiological properties from other sensorin-A-expressing neurons. Neurons in all of the clusters have relatively high mechanosensory thresholds, responding preferentially to threatening or noxious stimuli. Synaptic outputs to target cells having defensive functions support a nociceptive role, as does peripheral sensitization following noxious stimulation, although additional functions are likely in some clusters. Interesting questions arise from observations that mRNA for sensorin-A is present not only in the somata but also in synaptic regions, connectives, and peripheral fibers.
Hereditary coproporphyria is an autosomal dominant disorder resulting from the half-normal activity of coproporphyrinogen oxidase (CPO), a mitochondrial enzyme catalyzing the antepenultimate step in heme biosynthesis. The mechanism by which CPO catalyzes oxidative decarboxylation, in an extraordinary metaland cofactor-independent manner, is poorly understood. Here, we report the crystal structure of human CPO at 1.58-Å resolution. The structure reveals a previously uncharacterized tertiary topology comprising an unusually flat seven-stranded -sheet sandwiched by ␣-helices. In the biologically active dimer (KD ؍ 5 ؋ 10 ؊7 M), one monomer rotates relative to the second by Ϸ40°to create an intersubunit interface in close proximity to two independent enzymatic sites. The unexpected finding of citrate at the active site allows us to assign Ser-244, His-258, Asn-260, Arg-262, Asp-282, and Arg-332 as residues mediating substrate recognition and decarboxylation. We favor a mechanism in which oxygen serves as the immediate electron acceptor, and a substrate radical or a carbanion with substantial radical character participates in catalysis. Although several mutations in the CPO gene have been described, the molecular basis for how these alterations diminish enzyme activity is unknown. We show that deletion of residues (392-418) encoded by exon six disrupts dimerization. Conversely, harderoporphyria-causing K404E mutation precludes a type I -turn from retaining the substrate for the second decarboxylation cycle. Together, these findings resolve several questions regarding CPO catalysis and provide insights into hereditary coproporphyria.coproporphyrinogen oxidase ͉ oxidative decarboxylation ͉ mitochondria ͉ x-ray crystallography T he terminal three steps of heme biosynthesis occur within the mitochondria (1, 2). First, coproporphyrinogen III is converted to protoporphyrinogen IX in the intermembrane space (3, 4) by coproporphyrinogen oxidase (CPO) (5, 6). Thus, CPO contains an unusually long (110 residues) N-terminal targeting sequence, required for its import into the mitochondria (7,8). The substrate for CPO is generated in the cytosol (9) by uroporphyrinogen decarboxylase, and the precise mechanism by which it enters the mitochondria remains to be elucidated. Second, protoporphyrinogen oxidase mediates the six electron oxidation of protoporphyrinogen to protoporphyrin IX. This enzyme is localized to the cytoplasmic side of the inner mitochondrial membrane. Third, ferrochelatase inserts the ferrous iron to generate heme within the matrix of the mitochondria. Hence, the heme biosynthetic pathway is not only partitioned between mitochondria and cytosol, but the last three enzymes are compartmentalized within the mitochondria.Partial deficiency of CPO leads to hereditary coproporphyria (HCP), an acute hepatic porphyria inherited in an autosomal dominant fashion (10-12). The disease is characterized by abdominal pain, neuropsychiatric symptoms, and͞or cutaneous photosensitivity (13). If diagnosed early, HCP can be treat...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.