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Some of the fascinating features of voltage-sensing domains (VSD) in voltage-gated cation channels (VGCC) are their modular nature and adaptability. Here we examined the VSD promiscuity of VGCC, using non-toxin gating-modifiers, NH17 and NH29, which share closely related structures and stabilize Kv7.2 potassium channels, in the closed and open state, respectively. NH17 and NH29 exert opposite gating-modifier effects on TRPV1 channels,
operating respectively, as an activator and a blocker of TRPV1 currents. Combined mutagenesis and electrophysiology, structural homology modeling, molecular docking and molecular dynamics simulation indicate that both compounds target the VSD of TRPV1 channels, which like vanilloids are involved in π-π stacking, H-bonding and hydrophobic interactions. Reflecting the VSD promiscuity, they also affect the lone VSD proton channel mVSOP. Remarkably, NH29 alleviates neuropathic pain in rats, suggesting that sometimes, promiscuous VSD ligands may be therapeutically beneficial. Thus, structurally related, yet different molecules can interact with the VSD of the same VGCC, while the same gating-modifier can promiscuously interact with different VGCC. Subtle differences at the VSD-ligand interface will dictate whether the gating-modifier stabilizes channels in either the closed or the open state.

Neurons and networks must constantly rebuild themselves in response to the continual and ongoing turnover of all of the ion channels and receptors that are necessary for neuronal signaling. A good deal of work argues that stable neuronal and network function arises from homeostatic negative feedback mechanisms. Nonetheless, while these mechanisms can produce a target activity or performance, they are also consistent with a good deal of recent theoretical and experimental work that shows that similar circuit outputs can be produced with highly variable circuit parameters. This work argues that the nervous system of each healthy individual has found a set of different solutions that give “good enough circuit performance. I will describe new computational models (O’Leary et al., PNAS 2013; Neuron in press, 2014) for cellular homeostasis that give insight into a variety of experimental observations, including correlations in the expression of ion channel genes. In response to perturbation these homeostatic models usually compensate for perturbations, but some perturbations elude compensation. Moreover, situations can arise in which the homeostatic mechanisms result in aberrant behavior, such as may occur in disease.