2020.12.18

TACAN Is an Ion Channel Involved in Sensing Mechanical Pain

Lou Beaulieu-Laroche 1Marine Christin 1Annmarie Donoghue 2Francina Agosti 3Noosha Yousefpour 4Hugues Petitjean 1Albena Davidova 1Craig Stanton 1Uzair Khan 5Connor Dietz 5Elise Faure 6Tarheen Fatima 1Amanda MacPherson 5Stephanie Mouchbahani-Constance 1Daniel G Bisson 7Lisbet Haglund 7Jean A Ouellet 8Laura S Stone 9Jonathan Samson 10Mary-Jo Smith 11Kjetil Ask 12Alfredo Ribeiro-da-Silva 4Rikard Blunck 13Kate Poole 14Emmanuel Bourinet 3Reza Sharif-Naeini 15

Abstract

Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying essential physiological functions such as touch and pain sensing, hearing, and proprioception. Although the mechanisms for some of these functions have been identified, the molecules essential to the sense of pain have remained elusive. Here we report identification of TACAN (Tmem120A), an ion channel involved in sensing mechanical pain. TACAN is expressed in a subset of nociceptors, and its heterologous expression increases mechanically evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel. Finally, a nociceptor-specific inducible knockout of TACAN decreases the mechanosensitivity of nociceptors and reduces behavioral responses to painful mechanical stimuli but not to thermal or touch stimuli. We propose that TACAN is an ion channel that contributes to sensing mechanical pain.

Keywords: TACAN; bilayer; ion channel; mechanosensitive; mechanotransduction; nociceptor; pain; patch clamp; pillar.

Journal Club-2020.12.11

GRPR/Extracellular SignaleRegulated Kinase and NPRA/Extracellular SignaleRegulated Kinase Signaling Pathways Play a Critical Role in Spinal Transmission of Chronic Itch

Abstract

Intractable or recurrent chronic itch greatly reduces the patients’ QOL and impairs their daily activities. In this study, we investigated whether there are certain key signaling molecules downstream of the recently identified peptides mediating itch in the spinal cord. RNA sequencing analysis of mouse spinal cord in chronic itch models induced by squaric acid dibutylester and imiquimod showed that extracellular signaleregulated kinase (ERK) 1/2 cascade is the most significantly upregulated gene cluster in both models. In four different mouse models of chronic itch, sustained ERK phosphorylation was detected mainly in spinal neurons, and MAPK/ERK kinase inhibitors significantly inhibited chronic itch in these models. Phosphorylated ERK was observed in the interneurons expressing the receptors of different neuropeptides for itch, including gastrin-releasing peptide receptor, natriuretic peptide receptor A, neuromedin B receptor, and sst2A. Blocking gastrin-releasing peptide receptor and natriuretic peptide receptor A by genetic approaches or toxins in mice significantly attenuated or ablated spinal phosphorylated ERK. When human embryonic kidney 293T cells transfected with these receptors were exposed to their respective agonists, ERK was the most significantly activated intracellular signaling molecule. Together, our work showed that phosphorylated ERK is a unique marker for itch signal transmission in the spinal cord and an attractive target for the treatment of chronic itch.

2020.12.05 Journal Club

Behavioral characterization of a CRISPR-generated TRPA1 knockout rat in models of pain, itch, and asthma

Rebecca M. Reese1,4, Michelle Dourado1,4, Keith Anderson 3, Søren Warming 3, Kimberly L. Stark1, Alessia Balestrini2, eric Suto2, Wyne Lee2, Lorena Riol-Blanco2, Shannon D. Shields& David H. Hackos1*

The transient receptor potential (TRP) superfamily of ion channels has garnered significant attention by the pharmaceutical industry. In particular, TRP channels showing high levels of expression in sensory neurons such as TRPV1, TRPA1, and TRPM8, have been considered as targets for indications where sensory neurons play a fundamental role, such as pain, itch, and asthma. Modeling these indications in rodents is challenging, especially in mice. The rat is the preferred species for pharmacological studies
in pain, itch, and asthma, but until recently, genetic manipulation of the rat has been technically challenging. Here, using CRISPR technology, we have generated a TRPA1 KO rat to enable more sophisticated modeling of pain, itch, and asthma. We present a detailed phenotyping of the TRPA1
KO rat in models of pain, itch, and asthma that have previously only been investigated in the mouse. With the exception of nociception induced by direct TRPA1 activation, we have found that the TRPA1 KO rat shows apparently normal behavioral responses in multiple models of pain and itch. Immune cell infiltration into the lung in the rat OVA model of asthma, on the other hand, appears to be dependent on TRPA1, similar to was has been observed in TRPA1 KO mice. Our hope is that the TRPA1 KO rat will become a useful tool in further studies of TRPA1 as a drug target.

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