title: In silico determination of the effect of multi-target drugs on calcium dynamics signaling network underlying sea urchin spermatozoa motility.
abstract: The motility of spermatozoa of both Lytechinus pictus and Strongylocentrotus purpuratus sea urchin species is modulated by the egg-derived decapeptide speract via an oscillatory [Ca2+]-dependent signaling pathway. Comprehension of this pathway is hence directly related to the understanding of regulated sperm swimming. Niflumic acid (NFA), a nonsteroidal anti-inflammatory drug alters several ion channels. Though unspecific, NFA profoundly affects how sea urchin sperm respond to speract, increasing the [Ca2+]i oscillation period, amplitude, peak and average level values of the responses in immobilized and swimming cells. A previous logical network model we developed for the [Ca2+] dynamics of speract signaling cascade in sea urchin sperm allows integrated dissection of individual and multiple actions of NFA. Among the channels affected by NFA are: hyperpolarization-activated and cyclic nucleotide gated Na+ channels (HCN), [Ca2+]-dependent Cl- channels (CaCC) and [Ca2+]-dependent K+ channels (CaKC), all present in the sea urchin genome. Here, using our model we investigated the effect of blocking in silico HCN and CaCC channels suggested by experiments. Regarding CaKC channels, arguments can be provided for either their blockage or activation by NFA. Our study yielded two scenarios compliant with experimental observations: i) under CaKC inhibition, this [Ca2+]-dependent K+ channel should be different from the Slo1 channel and ii) under activation of the CaKC channel, another [Ca2+] channel not considered previously in the network is required, such as the pH-dependent CatSper channel. Additionally, our findings predict cause-effect relations resulting from a selective inhibition of those channels. Knowledge of these relations may be of consequence for a variety of electrophysiological studies and have an impact on drug related investigations. Our study contributes to a better grasp of the network dynamics and suggests further experimental work.
authors.affiliation: Instituto de Ciencias Físicas, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México; Centro de Ciencias de la Complejidad, Ciudad Universitaria, México, México; Instituto Nacional de Medicina Genómica, Arenal Tepepan, Tlalpan, México.
authors.forename: Jesús
authors.initials: J
authors.lastname: Espinal-Enríquez
authors.affiliation: Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México.
authors.forename: Alberto
authors.initials: A
authors.lastname: Darszon
authors.affiliation: Laboratorio Nacional de Microscopía Avanzada, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México.
authors.forename: Adán
authors.initials: A
authors.lastname: Guerrero
authors.affiliation: Instituto de Ciencias Físicas, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México; Centro de Ciencias de la Complejidad, Ciudad Universitaria, México, México; Centro Internacional de Ciencias, Cuernavaca, Morelos, México.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Martínez-Mekler
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D003198:Computer Simulation; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009544:Niflumic Acid / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000378:metabolism; D012617:Sea Urchins; D013081:Sperm Motility / Q000187:drug effects*; D013094:Spermatozoa / Q000187:drug effects / Q000502:physiology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002121:Calcium Channel Blockers; D018118:Chloride Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009842:Oligopeptides; D024681:Potassium Channels, Calcium-Activated; D009544:Niflumic Acid; C028364:speract; D002118:Calcium