G‐protein‐coupled receptor‐based sensors for imaging neurochemicals with high sensitivity and specificity

Abstract

Neurotransmitters and neuromodulators are key neurochemicals that mediate cell-cell communication, maintain the body's homeostasis, and control a wide range of biological processes. Thus, dysregulation of neurochemical signaling is associated with a range of psychiatric disorders and neurological diseases. Understanding the physiological and pathophysiological functions of neurochemicals, particularly in complex biological systems in vivo, requires tools that can probe their dynamics with high sensitivity and specificity. Recently, genetically encoded fluorescent sensors for visualizing specific neurochemicals were developed by coupling neurochemical-sensing G-protein-coupled receptors (GPCRs) with a circular-permutated fluorescent protein. These GPCR-based sensors can monitor the dynamics of neurochemicals in behaving animals with high spatiotemporal resolution. Here, we review recent progress regarding the development and application of GPCR-based sensors for imaging neurochemicals, and we discuss future perspectives.

Genetically encoded sensors enable micro- and nano-scopic decoding of transmission in healthy and diseased brains

“…The development of genetically encoded transmitter sensors offers opportunities to make groundbreaking advances in neuromodulation research. While many researchers use the new sensors merely as sensitive detectors to monitor dynamic neuromodulatory signals, as advocated by recent reviews [22,23,42,43], these sensors could actually do more than that. The new genetically encoded neuromodulatory sensors, fortuitously, emit a large amount of photons with their fluorescence responses being largely independent of the expression levels [29,[32][33][34].…”

A DNA-based optical nanosensor for in vivo imaging of acetylcholine in the peripheral nervous system

“…We chose nicotinic ACh receptors as the binding target because it is used broadly across the body including the CNS and sympathetic, parasympathetic, and somatic PNS and because of its well-studied binding affinity to BTX 27,31 . Successful employment of the same receptors as the targeting region is also demonstrated in CNiFER sensors 6,50 . Concerns may arise regarding whether the binding between BTX and ACh receptors would block normal ACh signal transmission and negatively affect or harm the imaging subject.…”

The entorhinal cortex modulates trace fear memory formation and neuroplasticity in the lateral amygdala via cholecystokinin

“…As CCK-8s is a potent agonist of both CCKAR and CCKBR, we selected CCK-4, which is a preferred CCKBR agonist (Berna et al, 2007). To monitor CCK signaling in vivo, we expressed a G protein-coupled receptor (GPCR)-activation-based CCK sensor (GRABCCK, AAV-hSyn-CCK2.0) in the LA of CCK -/mice (Jing et al, 2019). Using this model, binding of the GPCR CCKBR with endogenous or exogenous CCK results in increased fluorescence intensity, which we measured by fiber photometry in the LA (Figure S2a).…”