Molecular Tools for Targeted Control of Nerve Cell Electrical Activity. Part II

Abstract

In modern life sciences, the issue of a specific, exogenously directed manipulation of a cell's biochemistry is a highly topical one. In the case of electrically excitable cells, the aim of the manipulation is to control the cells' electrical activity, with the result being either excitation with subsequent generation of an action potential or inhibition and suppression of the excitatory currents. The techniques of electrical activity stimulation are of particular significance in tackling the most challenging basic problem: figuring out how the nervous system of higher multicellular organisms functions. At this juncture, when neuroscience is gradually abandoning the reductionist approach in favor of the direct investigation of complex neuronal systems, minimally invasive methods for brain tissue stimulation are becoming the basic element in the toolbox of those involved in the field. In this review, we describe three approaches that are based on the delivery of exogenous, genetically encoded molecules sensitive to external stimuli into the nervous tissue. These approaches include optogenetics (overviewed in Part I), as well as chemogenetics and thermogenetics (described here, in Part II), which is significantly different not only in the nature of the stimuli and structure of the appropriate effector proteins, but also in the details of experimental applications. The latter circumstance is an indication that these are rather complementary than competing techniques.

Keywords: GPCR; action potential; channelrhodopsin; chemogenetics; chemoreceptors; ion channels; membrane voltage; neural activity stimulation; neural excitation; neural inhibition; neurointerface; optogenetics; thermogenetics.

Fig. 1

The TRP superfamily and temperature sensitivity of its chosen members. The top of the figure shows seven TRP-receptor families subdivided into two groups. In the bottom row, there are thermogenetically relevant molecules originating from three TRP families. The color scheme depicts the temperatures needed for the activation of the corresponding TRPs

Fig. 2

The timeline showing the emergence of diverse chemogenetic approaches. The main types of chemogenetic actuators, their wild-type predecessors (top panel: GPCR-based ones; bottom panel: the ones based on ligand-gated ion channels (LGICs)), and the molecular mechanisms providing their activation are shown