ZBTB20 Regulates Nociception And Pain Sensation By Modulating TRP Channel Expression In Nociceptive Sensory Neurons

The mechanism of pain is one of the hot spots in the field of neuroscience. In mammals, the small-diameter neurons in the dorsal root ganglion (DRG) are primary nociceptive neurons that can sense and transmit nociceptive signal. There are two major subsets of small DRG neurons. One subset is peptidergic, which expresses receptor tyrosine kinase TrkA, the receptor of nerve growth factor, and synthesizes neuropeptides like calcitonin-gene related peptide (CGRP) and substance P. The other is nonpeptidergic, which expresses the c-Ret neurotrophin receptor, and responds to glial-derived neurotrophic factor. Most c-Ret-positive neurons are capable of binding the isolectin IB4 and express Mas-related G-protein coupled receptors (Mrgpr), and specific purinergic receptor subtypes, notably P2X3.Pain sensation is initiated by the detection of noxious stimuli through specialized transduction ion channels and receptors in nociceptive sensory neurons in DRG. Transient receptor potential (TRP) channels are the key sensory transducers that confer nociceptors distinct sensory modalities. TRP channels are temperature dependent ionic channels including TRPC, TRPV, TRPM, TRPML, TRPPP and TRPA. As an endogenous transducer of noxious heat, TRPV1 is essential for selective modalities of pain sensation and tissue injury-induced thermal hyperalgesia. Furthermore, TRPM8 and TRPA1 putatively act as cold pain receptors. However, the regulatory mechanisms about their expression are poorly defined.Several transcription factors have been demonstrated to control the development and differentiation of nociceptive sensory neurons. The neuronal determination gene Neurogeninl (Ngnl) is required for the formation of most nociceptors. The homeobox gene Brn3a and the zinc-finger gene Klf7 are required for the expression of TrkA and the survival of nociceptors. Runxl, a Runt domain transcription factor, controls neuronal diversification within Ngnl-dependent TrkA neurons by repressing CGRP and substance P expression and coordinates the expression of many ion channels and receptors in nociceptors, including TRP class thermal receptors such as TRPV1 and TRPA1, the opioid receptor MOR and purine receptor P2X3. Furthermore, the transcription factor Tlx3 acts in combination with Runxl to control the development of a cohort of nociceptors, thermoceptors, and pruriceptors in mice. To date, the transcription factors that specifically regulate the differential expression of nociceptive TRP channels have not been identified.Zinc-finger and BTB domain containing protein 20 (ZBTB20, also known as DPZF, HOF and Zfp288) belongs to a subfamily of zinc-finger proteins containing C2H2 Kruppel-type zinc fingers and BTB/POZ domains. ZBTB20 is highly expressed in central nervous system and plays a critical role in hippocampal development and function, but its function in peripheral nervous system is rarely known. Here we show that the zinc finger protein ZBTB20 regulates TRP channels expression in nociceptors. ZBTB20 is highly expressed in nociceptive sensory neurons of DRG. Disruption of ZBTB20 in nociceptors led to a marked decrease in the expression levels of TRPV1, TRPA1, and TRPM8 and the response of calcium flux and whole-cell currents evoked by their respective specific agonists. Phenotypically, the mice lacking ZBTB20 specifically in nociceptors showed a defect in nociception and pain sensation in response to thermal, mechanical and inflammatory stimulation. Our findings point to ZBTB20 as a critical regulator of nociception and pain sensation by modulating TRP channels expression in nociceptors.