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Snake venoms are a mixture of pharmacologically active proteins and polypeptides that have led to the development of molecular probes and therapeutic agents. Here, we describe the structural and functional characterization of a novel neurotoxin, haditoxin, from the venom of Ophiophagus hannah (King cobra). Haditoxin exhibited novel pharmacology with antagonism toward muscle (alphabetagammadelta) and neuronal (alpha(7), alpha(3)beta(2), and alpha(4)beta(2)) nicotinic acetylcholine receptors (nAChRs) with highest affinity for alpha(7)-nAChRs. The high resolution (1.5 A) crystal structure revealed haditoxin to be a homodimer, like kappa-neurotoxins, which target neuronal alpha(3)beta(2)- and alpha(4)beta(2)-nAChRs. Interestingly however, the monomeric subunits of haditoxin were composed of a three-finger protein fold typical of curaremimetic short-chain alpha-neurotoxins. Biochemical studies confirmed that it existed as a non-covalent dimer species in solution. Its structural similarity to short-chain alpha-neurotoxins and kappa-neurotoxins notwithstanding, haditoxin exhibited unique blockade of alpha(7)-nAChRs (IC(50) 180 nm), which is recognized by neither short-chain alpha-neurotoxins nor kappa-neurotoxins. This is the first report of a dimeric short-chain alpha-neurotoxin interacting with neuronal alpha(7)-nAChRs as well as the first homodimeric three-finger toxin to interact with muscle nAChRs.
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http://dx.doi.org/10.1074/jbc.M109.074161 | DOI Listing |
Trans R Soc Trop Med Hyg
November 2024
Department of Immunology, Institute of Endemic Diseases, University of Khartoum, P.O. Box 11463, Khartoum, Sudan.
Background: Neurotoxicity is a common feature of elapid snake envenomation. There are limited studies on the toxicity of Naja nubiae venom, the Nubian spitting cobra, from north-east Africa.
Methods: We used the chick biventer cervicis nerve-muscle preparation to demonstrate the neurotoxic effect of N.
Toxins (Basel)
October 2024
Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Ohlebergsweg 12, 35392 Giessen, Germany.
"True" cobras (genus ) are among the venomous snakes most frequently involved in snakebite accidents in Africa and Asia. The Cape cobra () is one of the African cobras of highest medical importance, but much remains to be learned about its venom. Here, we used a shotgun proteomics approach to better understand the qualitative composition of venom and tested its cytotoxicity and protease activity as well as its effect on intracellular Ca release and NO synthesis.
View Article and Find Full Text PDFBiochem Biophys Res Commun
November 2024
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, UNAM, Apartado Postal 510-3, Cuernavaca, Morelos, 61500, Mexico. Electronic address:
Antivenoms are essential in the treatment of the neurotoxicity caused by elapid snakebites. However, there are elapid neurotoxins, e.g.
View Article and Find Full Text PDFMol Neurobiol
October 2024
Hebei Research Center of the Basic Discipline of Cell Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Key Laboratory of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, 050024, China.
Intestinal dysbiosis plays a critical role in the pathogenesis of Parkinson's disease (PD), and probiotics have emerged as potential modulators of central nervous system function through the microbiota-gut-brain axis. This study aimed to elucidate the anti-inflammatory effects and underlying mechanisms of the probiotic strain Bifidobacterium animalis subsp. lactis NJ241 (NJ241) in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
View Article and Find Full Text PDFNeurochem Int
March 2024
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab, India. Electronic address:
Human gut microbiota are thought to affect different physiological processes in the body, including brain functions. Gut dysbiosis has been linked to the progression of Parkinson's disease (PD) and thus, restoring the healthy gut microbiota with supplementation of putative probiotic strains can confer some benefits in PD. In the current study, we explored the neuroprotective potential of Bifidobacterium breve Bif11 supplementation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treated female Sprague Dawley rats.
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