<i>In Silico</i> Determination of the Effect of Multi-Target Drugs on Calcium Dynamics Signaling Network Underlying Sea Urchin Spermatozoa Motility

<div><p>The motility of spermatozoa of both <i>Lytechinus pictus</i> and <i>Strongylocentrotus purpuratus</i> 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>_i</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 (<i>HCN</i>), [Ca²⁺]-dependent Cl⁻ channels (<i>CaCC</i>) and [Ca²⁺]-dependent K⁺ channels (<i>CaKC</i>), all present in the sea urchin genome. Here, using our model we investigated the effect of blocking <i>in silico HCN</i> and <i>CaCC</i> channels suggested by experiments. Regarding <i>CaKC</i> channels, arguments can be provided for either their blockage or activation by NFA. Our study yielded two scenarios compliant with experimental observations: i) under <i>CaKC</i> inhibition, this [Ca²⁺]-dependent K⁺ channel should be different from the <i>Slo1</i> channel and ii) under activation of the <i>CaKC</i> channel, another [Ca²⁺] channel not considered previously in the network is required, such as the pH-dependent <i>CatSper</i> 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.</p>