Abstract
Our understanding of the general principles of the polymodal regulation of transient receptor potential (TRP) ion channels has grown impressively in recent years as a result of intense efforts in protein structure determination by cryo-electron microscopy. In particular, the high-resolution structures of various TRP channels captured in different conformations, a number of them determined in a membrane mimetic environment, have yielded valuable insights into their architecture, gating properties and the sites of their interactions with annular and regulatory lipids. The correct repertoire of these channels is, however, organized by supramolecular complexes that involve the localization of signaling proteins to sites of action, ensuring the specificity and speed of signal transduction events. As such, TRP ankyrin 1 (TRPA1), a major player involved in various pain conditions, localizes into cholesterol-rich sensory membrane microdomains, physically interacts with calmodulin, associates with the scaffolding A-kinase anchoring protein (AKAP) and forms functional complexes with the related TRPV1 channel. This perspective will contextualize the recent biochemical and functional studies with emerging structural data with the aim of enabling a more thorough interpretation of the results, which may ultimately help to understand the roles of TRPA1 under various physiological and pathophysiological pain conditions. We demonstrate that an alteration to the putative lipid-binding site containing a residue polymorphism associated with human asthma affects the cold sensitivity of TRPA1. Moreover, we present evidence that TRPA1 can interact with AKAP to prime the channel for opening. The structural bases underlying these interactions remain unclear and are definitely worth the attention of future studies.
Highlights
The transmembrane domain of TRP ankyrin 1 (TRPA1) is composed of the voltage sensor-like domain (VSLD) formed by a bundle of four antiparallel helices, S1–S4, and the pore domain arranged in a domainswap manner
There are at least two sites with separate functions from which the activity of TRPA1 can be regulated by membrane phosphatidylinositol4,5-bisphosphate (PIP2) or other phosphoinositides: the first, formed by the intracellular part of VSLD and contributed to by K989 from the Transient Receptor Potential (TRP)-like domain (Samad et al, 2011; Witschas et al, 2015; Zimova et al, 2018), and the second localized between adjacent subunits (T1003–P1034), capable of directly affecting the gating of the channel through the S4-S5 linker and R975 from the TRP-like domain (Macikova et al, 2019)
We hypothesized that arginine at position 1018 may alter the affinity of PIP2 to TRPA1, and thereby influence the activation of the channel by other stimuli, by heat or cold temperatures
Summary
The Transient Receptor Potential (TRP) Ankyrin subtype 1 (TRPA1), originally called ANKTM1 (Story et al, 2003), is a cation channel expressed in a subset of dorsal root, trigeminal and visceral primary sensory neurons (Bautista et al, 2006; Kwan et al, 2006), and in non-neuronal cells such as keratinocytes (Kwan et al, 2006), fibroblasts (Jaquemar et al, 1999), odontoblasts (El Karim et al, 2011), astroglia (Shigetomi et al, 2011), Schwann cells (De Logu et al, 2017), endothelial cells, and arterial vessels (Kwan et al, 2009). Some other groups did not observe any cold activation (Jordt et al, 2004; Zurborg et al, 2007; Knowlton et al, 2010; Cordero-Morales et al, 2011; Chen et al, 2013) This is clearly not the whole story, and further intensive investigation is required to determine the specific role of mammalian TRPA1 as a temperature sensor (Sinica et al, 2019). We demonstrate that AKAP, the scaffolding A-kinase anchoring protein that is necessary for the effective phosphorylation of TRPA1 by protein kinases A and C, potentiates the channel at negative membrane potentials, suggesting the existence of basal phosphorylation or a direct effect of AKAP on TRPA1 These primary results provide potentially important information indicating that the membrane proximal part of the C-terminus of TRPA1 may form a hot spot contributing to a highly effective regulation of TRPA1, additional structural/functional considerations are necessary to characterize the channel in its full physiological context
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