TRP Channels as Therapeutic Targets

From Basic Science to Clinical Use

Arpad Szallasi

• Publisher: Academic Press
• Year: 2015
• eBook ISBN: 9780124200791
• Topic: Medicine
• Subtopic: Pharmacology

TRP Channels as Therapeutic Targets: From Basic Science to Clinical Use is authored by experts across academia and industry, providing readers with a complete picture of the therapeutic potential and challenges associated with using TRP channels as drug targets.This book offers a unique clinical approach by covering compounds that target TRP channels in pre-clinical and clinical phases, also offering a discussion of TRP channels as biomarkers.An entire section is devoted to the novel and innovative uses of these channels across a variety of diseases, offering strategies that can be used to overcome the adverse effects of first generation TRPV1 antagonists.Intended for all researchers and clinicians working toward the development of successful drugs targeting TRP channels, this book is an essential resource chocked full of the latest clinical data and findings.- Contains comprehensive coverage of TRP channels as therapeutic targets, from emerging clinical indications to completed clinical trials- Discusses TRP channels as validated targets, ranging from obesity and diabetes through cancer and respiratory disorders, kidney diseases, hypertension, neurodegenerative disorders, and more- Provides critical analysis of the complications and side effects that have surfaced during clinical trials, offering evidence-based suggestions for overcoming them

Chapter 1

An Introduction to Transient Receptor Potential Ion Channels and Their Roles in Disease

Michael J. Caterina^1,2,3,4,* ¹ Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
² Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
³ Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
⁴ Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
^* Corresponding author: [email protected]

Abstract

The transient receptor potential (TRP) cation channel family consists of seven subfamilies that are widely expressed in mammalian tissues. By mediating flux of calcium, sodium, and other cations across cell membranes, in addition to nonionic signaling mechanisms, these channels contribute to many sensory and nonsensory processes throughout the body. Abnormalities in TRP channel function, whether a consequence of mutations in their sequence, alterations in their expression levels, or changes in their myriad regulators, have been associated with numerous disease states ranging from chronic pain to cardiovascular disease, skeletal abnormalities, and cancer. Such prevalent involvement in disease stems not only from the ubiquity of TRP channels but also from their complex pattern of polymodal gating. The connection between TRP channels and disease creates numerous opportunities for therapeutic intervention at these channels, whether through inhibition, activation, or co-opting of their ability to transport cations to alter the course of pathophysiological processes.

Keywords

Transient receptor potential

Ion channel

Channelopathy

Pain

Calcium

Outline

Discovery and General Properties of TRP Channels 2

TRP Channels in Normal Physiology 4

TRP Channels and Sensory Physiology 4

TRP Channels and Cardiovascular Function 5

TRP Channels and Gastrointestinal Function 5

TRP Channels and Urological Function 5

TRP Channels and the Brain 5

TRP Channels and Immune Function 5

TRP Channels and Development 6

TRP Channels and Disease 6

Therapeutic Strategies Based on TRP Channel Modulation 9

Acknowledgment 10

References 10

Discovery and General Properties of TRP Channels

The diverse repertoire of ion channels expressed in mammalian and nonmammalian species is encoded by a multitude of gene families. Among these, the transient receptor potential (TRP) ion channel family exhibits an especially prevalent and complex link with disease. Fittingly for the theme of this book, the TRP channel name emerged as a consequence of a disease state, although the victims of this disease were not human beings, but rather members of a line of visually impaired fruit flies [1]. Electroretinograms recorded from photoreceptors of these flies revealed that the electrical response to a light pulse (receptor potential), instead of remaining robust throughout a pulse of several seconds, decayed prematurely. Subsequent molecular and physiological studies revealed that the gene mutated in these so-called transient receptor potential (trp) flies encoded an ion channel subunit that, together with a homologous channel subunit, TRPL, forms the functional photoreceptor channel. This channel is not gated directly by light, but rather is activated by a G protein-coupled phospholipase C signaling pathway following the photoisomerization of the light receptor protein, rhodopsin.

Following the identification of the Drosophila TRP channel, numerous homologous proteins were discovered, both in invertebrate species, such as fruit flies and nematodes, and in vertebrate species from fish to mammals [2]. Based on their domain structure and details of their sequences, members of the TRP channel family can be divided into seven subfamilies: TRPA (ankyrin, 1 human member), TRPC (canonical, 6 human members, plus 1 human pseudogene), TRPM (melastatin, 8 human members), TRPML (mucolipin, 3 human members), TRPN (NompC, no human members), TRPP (polycystin, 3 human members), and TRPV (vanilloid, 6 human members). There is also a distantly related family, TRPY, found in yeast. Functional TRP channels consist of homomeric or heteromeric tetramers of subunits from these subfamilies. The domain structure of an example TRP channel subunit, TRPV1, is shown in Figure 1.1a. A common structural feature of all TRP channel subunits is a core of six transmembrane domains (S1-S6), flanked by intracellular amino- and carboxyl-termini. Between S5 and S6 there is a complex pore-loop structure, which breaches the extracellular plane of the plasma membrane and forms the ion selectivity filter. This overall architecture resembles that of the voltage-gated and cyclic nucleotide-gated channel families. The TRPC, TRPM, TRPV, TRPA, and TRPN subfamilies, referred to as Group I TRP channels, resemble one another more closely than they do the TRPP or TRPML subfamilies, which are classified as Group II. Two features found among most Group I TRP channels include a TRP box homology element (absent in the TRPA subfamily), just distal to the sixth transmembrane domain, that participates in channel multimerization and modulation of gating, and a string of 4-16 sequential ankyrin repeat domains in the amino terminus (absent in the TRPM subfamily) that serves as a site of channel regulation (Figure 1.1a). Several TRPM subfamily members also contain kinase or nucleotide binding domains within their carboxyl termini and are therefore referred to as “chanzymes.” Ion flux through TRP channels occurs via a central pore lined by the pore loop domains of the four channel subunits (Figure 1.1b). All known TRP channels are selective for cations, although their degree of discrimination among cations can vary. For example, although some channels such as TRPV5 and TRPV6 are highly selective for Ca^{2 +}, and TRPM4 and TRPM5 are relatively Ca^{2 +} impermeant, most TRP channels are nonselective cation channels that can mediate flux of multiple monovalent and divalent cations [3]. Whereas most of these channels function at the plasma membrane, some are also found in organellar membranes. For example, TRPM2, TRPML, and TRPV2 channels can reside and function within the endolysosomal pathway [4]. A higher-resolution understanding of structural features of TRP channels has recently emerged with the solution of the atomic-level structure of one family member, TRPV1, by cryo-electron microscopy (Figure 1.1b and c) [5,6]. A few details and implications of this important advance will be described later in this chapter.

Figure 1.1 Representative TRP channel structure. (a) Domain map of a TRPV1 subunit. Amino terminus is at left. (b) TRPV1 holochannel structure in the apo (closed) state, solved by cryo-electron microscopy. Each subunit is in a different color. At left the channel is viewed from the side, illustrating distinct sites at which several agonists and regulators bind to allosterically control gating. At right, the transmembrane portion of the channel is viewed from the bottom and illustrates the separation between the S1-S4 domain and the S5-pore loop-S6 domain that forms the pore module lining the central pore axis (RTX, resiniferatoxin; DkTx, tarantula double-knot toxin). (c) Comparison of the TRPV1 pore module in the apo form (left) vs. a strongly activated state (right) evoked by a combination of RTX and DkTx. Path available for ion permeation is marked by dotted volume. For clarity, only two opposing subunits are shown. Sites of maximal constriction (G643 in the upper pore and I679 in the lower pore) are indicated. Note widening of both constrictions on activation. Modified, with permission, from Liao et al. [3] and Cao et al. [4].

TRP Channels in Normal Physiology

TRP channels as a family are broadly expressed in mammalian tissues. In fact, every cell in the body likely expresses at least one family member, and often more. Moreover, these channels can be activated by a number of heterogeneous stimuli, including a plethora of endogenous and exogenous chemical ligands, physical stimuli such as temperature and mechanical force, free cytosolic Ca^{2 +} ions, depletion of endoplasmic reticulum Ca^{2 +} stores, and many others. It should therefore not be surprising that these channels have been linked to numerous physiological functions. The following examples provide a glimpse into the ubiquitous involvement of TRP channels in the fundamental processes of life. As will be emphasized later in this chapter, and throughout this book, the pervasiveness of TRP channels in normal mammalian biology sets the stage for them to serve as contributors to, modulators of, or even primary causes of numerous human diseases.

TRP Channels and Sensory Physiology

Perhaps the best understood physiological functions of TRP channels are in the realm of sensory signal transduction. Just as the Drosophila TRP channel is a key effector in phototransduction, many other TRP channels serve either as primary transducers of environmental stimuli or as amplifiers or modulators of signals transduced by other receptors. The most extensively studied example from mammalian systems is TRPV1, a channel expressed at disproportionately high levels in a subpopulation of primary afferent nociceptors, sensory neurons that trigger the perception of pain [7]. TRPV1 was discovered on the basis of, and derives its name from, its ability to be gated by painful vanilloid compounds such as capsaicin (the main pungent ingredient in chili peppers) and resiniferatoxin (a highly potent irritant produced in the latex of Euphorbia plant species). Functional studies subsequently...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• Chapter 1: An Introduction to Transient Receptor Potential Ion Channels and Their Roles in Disease
• Chapter 2: Transient Receptor Potential Dysfunctions in Hereditary Diseases: TRP Channelopathies and Beyond
• Chapter 3: The Role of TRPV1 in Acquired Diseases: Therapeutic Potential of TRPV1 Modulators
• Chapter 4: TRP Gene Polymorphism and Disease Risk
• Chapter 5: Use of Topical Capsaicin for Pain Relief
• Chapter 6: TRPV1 Agonist Cytotoxicity for Chronic Pain Relief: From Mechanistic Understanding to Clinical Application
• Chapter 7: Intravesical Capsaicin and Resiniferatoxin for Bladder Disorders
• Chapter 8: Clinical and Preclinical Experience with TRPV1 Antagonists as Potential Analgesic Agents
• Chapter 9: Transient Receptor Potential Ankyrin 1 Channel Antagonists for Pain Relief
• Chapter 10: TRPA1 Antagonists as Potential Therapeutics for Respiratory Diseases
• Chapter 11: Is TRPV3 a Drug Target?—A Decade of Learning
• Chapter 12: Small Molecule Agonists and Antagonists of TRPV4
• Chapter 13: Potential Therapeutic Applications for TRPV4 Antagonists in Lung Disease
• Chapter 14: TRPM8 as a Target for Analgesia
• Chapter 15: Connecting TRP Channels and Cerebrovascular Diseases
• Chapter 16: Activating, Inhibiting, and Highjacking TRP Channels for Relief from Itch
• Chapter 17: Role of TRP Channels in Skin Diseases
• Chapter 18: Transient Receptor Potential Channels in Hypertension and Metabolic Syndrome
• Chapter 19: Transient Receptor Potential (TRP) Cation Channels in Diabetes
• Chapter 20: TRP Channels in Cardiovascular Disease
• Chapter 21: Targeting of Transient Receptor Potential Channels in Digestive Disease
• Chapter 22: TRP Channels in Cancer
• Chapter 23: Are Brain TRPs Viable Targets for Curing Neurodegenerative Disorders and Improving Mental Health?
• Chapter 24: Mucolipidosis Type IV: Part I
• Chapter 25: TRPML1-Dependent Processes as Therapeutic Targets
• Chapter 26: TRPs in Respiratory Disorders: Opportunities Beyond TRPA1
• Chapter 27: Conclusions
• Index