Modulation of intracellular calcium signaling by American pit viper venoms: A systematic review

Animal venoms specialized in incapacitating predators and prey have evolved to disrupt essential Ca²⁺ signaling pathways. One key group of venomous animals capable of such activity is the American pit vipers. Despite this, no summary of the literature on their venom-induced intracellular Ca²⁺ ([Ca²⁺]_i) modulatory activity has been performed. In this systematic review, we followed a rigorous double-blind screening process to review publications on American pit viper venoms and their effect on [Ca²⁺]_i. Search phrases were designed to capture all available literature across four databases, with 58 studies of interest retrieved. We identified a gap in the literature whereby only 18 out of the total 174 species of American pit vipers have been investigated for [Ca²⁺]_i signaling activity. It is hoped this review will increase understanding of the previously observed venom-induced [Ca²⁺]_i activity, spurring future research in an important field for biodiscovery and innate medical significance. Calcium ion (Ca²⁺) concentrations are tightly regulated in cells due to their significant role in numerous cellular processes and functions. Thus, dysregulation of Ca²⁺ signaling is detrimental to cell health. Animal venoms from the likes of Snakes, Arachnids, and Hymenoptera have evolved over thousands of years to incapacitate, deter, and disrupt both predator and prey physiology. Targeted evolution of unique venom components that disrupt essential Ca²⁺ signaling is thus unsurprising. One key group of venomous animals capable of such activity is the American pit vipers (subfamily: Crotalinae). Despite this, and in contrast to their considerable medical importance, no summary of the literature on their venom-induced intracellular Ca²⁺ ([Ca²⁺]_i) modulatory activity has been performed. Thus, the aim of this study was to provide the first systematic summary of American pit vipers [Ca²⁺]_i modulatory activity. We used a systematic approach to review available literature on American pit viper venoms and their effect on [Ca²⁺]_i. Search phrases were designed to capture all available literature, searches performed in four databases (Embase, PubMed, Scopus and Web of Science), and papers downloaded. Following a rigorous double-blind screening process in the Covidence software, 58 studies were retrieved from over 400 collated studies of interest. The data from each was investigated and summarized by genus, highlighting both research outcomes and methods utilized. We identified a gap in the literature whereby only 18 out of the total 174 species have been investigated for [Ca²⁺]_i signaling activity. <i>Bothrop</i>s and <i>Crotalus</i> have seen greater study with ten genera completely understudied. It is hoped this review will increase understanding of the previously observed venom-induced [Ca²⁺]_i activity to spur future research. Venom remains a critical area of research focus, both for its biodiscovery potential and its innate medical significance. There is a pressing need to understand the complexities of snake venom, as this is important not only for snake bite treatment, but also for developing novel therapeutics for treating of a wide range of diseases. Indeed, the study of venoms’ activity on important cellular processes, such as [Ca²⁺]_i signaling, is paramount for uncovering novel drug leads. This systematic review is a needed summary of the [Ca²⁺]_i modulatory activity of American pit viper venom, highlighting gaps in current knowledge, offering suggestions for future work, and ultimately paving the way for future studies that combat snakebites and develop therapeutics.