Abstract
The role of ion channels in neurons and muscles has been well characterized. However, recent work has demonstrated both the presence and necessity of ion channels in diverse cell types for morphological development. For example, mutations that disrupt ion channels give rise to abnormal structural development in species of flies, frogs, fish, mice, and humans. Furthermore, medications and recreational drugs that target ion channels are associated with higher incidence of birth defects in humans. In this review we establish the effects of several teratogens on development including epilepsy treatment drugs (topiramate, valproate, ethosuximide, phenobarbital, phenytoin, and carbamazepine), nicotine, heat, and cannabinoids. We then propose potential links between these teratogenic agents and ion channels with mechanistic insights from model organisms. Finally, we talk about the role of a particular ion channel, Kir2.1, in the formation and development of bone as an example of how ion channels can be used to uncover important processes in morphogenesis. Because ion channels are common targets of many currently used medications, understanding how ion channels impact morphological development will be important for prevention of birth defects. It is becoming increasingly clear that ion channels have functional roles outside of tissues that have been classically considered excitable.
Highlights
The correct development of a complex multicellular organism from a single fertilized egg requires cells communicating precisely
Heat is detected by heat-sensitive ion channels that include TRPV family members TRPV1 (>42◦C), TRPV2 (>52◦C), TRPV3 (34–38◦C), and TRPV4 (27–35◦C), Heat was first implicated as a teratogen when a wave of birth defects and abortions in
The discovery that ion channels actively participate in morphogenesis has opened up a new topic of developmental research: bioelectricity
Summary
The correct development of a complex multicellular organism from a single fertilized egg requires cells communicating precisely. Valproate, ethosuximide, phenobarbital, phenytoin, and carbamazepine are associated with significantly increased incidence of congenital malformations [reviewed in Veroniki et al (2017)]. Intrauterine exposure to topiramate is associated with increased incidence of congenital defects such as cleft lip and palate (Blotiere et al, 2019). These medications have some overlapping targets, but all of them impact electrical activity of cells. Phenytoin, phenobarbital, carbamazepine, and valproate all impact a cell’s potential for electrical activity, we suggest that changing a cell’s membrane potential may be a cause of their teratogenic influence on development
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