Transient receptor potential channels as therapeutic targets

Key Points

  • The role of transient receptor potential (TRP) channels is best understood in the pain area. As TRP channels are expressed on peripheral nociceptors, where pain is generated, it is hoped that TRP channel blockers will be devoid of the side effects that limit the use of analgesic agents that act on the central nervous system.

  • Several TRP cation channel subfamily V, member 1 (TRPV1) antagonists have advanced to clinical trials, but their side effects (which include hyperthermia and impaired noxious heat detection) have prevented any compounds from progressing beyond Phase II clinical trials.

  • TRPV3 antagonists have shown efficacy in models of neuropathic and inflammatory pain, and one antagonist has entered Phase I clinical trials.

  • An autosomal dominant mutation in the gene that encodes TRP cation channel subfamily A, member 1 (TRPA1) causes familial episodic pain syndrome. Indeed, TRPA1 antagonists have been shown to reduce cold hypersensitivity in rodent models of neuropathic pain without altering normal cold sensation in naive animals.

  • Several TRP channels (such as TRPV1, TRPV4 and TRP cation channel subfamily M, member 8 (TRPM8)) are expressed in the urinary bladder, where they presumably function as sensors of stretch and chemical irritation. TRPV1 and TRPV4 antagonists improve bladder function in rodent models of cystitis.

  • Populations of non-neuronal cells within the skin express many different types of TRP channels that are implicated in the regulation of several key cutaneous functions including skin-derived pruritus, proliferation, differentiation and inflammatory processes.

  • TRPA1 and TRPV1 serve as polymodal sensors in the mammalian respiratory tract that integrate varied inflammatory, oxidant and hazardous irritant stimuli to produce noxious sensations (for example, breathlessness, the urge to cough and nasopharyngeal pain) and respiratory reflexes such as coughing.

  • Several TRP channels — including members of TRP cation channel subfamily C (TRPC) and TRPV — influence the process of gas exchange by regulating airflow, blood flow and airway permeability.

  • Mutations in at least six of the 28 members of the TRP channel superfamily are associated with heritable genetic diseases in humans. These mutations have implicated TRP channels in many pathophysiological states and expanded our understanding of the physiological role of these channels.

  • The role of TRP channels in the brain remains to be elucidated, but it seems to be clear that some members of the superfamily are involved in neuronal excitability and neurotransmitter release. Genetic deletion of TRPC5 leads to an anxiolytic phenotype, whereas a point mutation in TRPC3 leads to ataxia.

  • TRP channels also serve important functions in other diseases that are not fully explored in this Review. For example, cancer and metabolic diseases will be particularly interesting to watch in the future.

Abstract

Transient receptor potential (TRP) cation channels have been among the most aggressively pursued drug targets over the past few years. Although the initial focus of research was on TRP channels that are expressed by nociceptors, there has been an upsurge in the amount of research that implicates TRP channels in other areas of physiology and pathophysiology, including the skin, bladder and pulmonary systems. In addition, mutations in genes encoding TRP channels are the cause of several inherited diseases that affect a variety of systems including the renal, skeletal and nervous system. This Review focuses on recent developments in the TRP channel-related field, and highlights potential opportunities for therapeutic intervention.

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Figure 1: Diversity in structure among TRP channel families.
Figure 2: TRP channels as nociceptors.
Figure 3: Roles of TRP channels in bladder functions.
Figure 4: TRP channels in human skin.
Figure 5: Diverse roles of TRP channels in the pathophysiology of the mammalian respiratory tract.

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Acknowledgements

We would like to thank B. Nilius for reading the manuscript and providing useful comments, and M. Trevisani for his help in compiling the TRPV1 antagonist clinical trials database.

Author information

Correspondence to Arpad Szallasi.

Ethics declarations

Competing interests

Magdalene M. Moran works at Hydra Biosciences and has stock options in the company. Hydra Biosciences focuses on TRP channels and has programmes on some of the TRP channels that are discussed in the Review.

Michael Allen McAlexander is a full-time employee at GlaxoSmithKline.

Arpad Szallasi is a paid consultant to two small biotechnology companies with active TRP channel drug discovery programmes.

Tamás Bíró declares no competing financial interests.

Supplementary information

Supplementary information S1 (box)

Clinical trials with TRPV1 antagonists (PDF 279 kb)

Supplementary information S2 (table)

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FURTHER INFORMATION

ClinicalTrials.gov website

Daewoong Pharmaceutical website

Drugs.com website

Drugs.com website

Glenmark Pharmaceuticals website

Japan Tobacco — Clinical Development of Pharmaceuticals (29 July 2010)

PharmEste website

Sanofi website

Glossary

Pruritus

Pruritus (also called an itch) is an unpleasant cutaneous sensation that is associated with an urge to scratch. Various categories of pruritus have been suggested, including pruriceptive itch (which arises from skin conditions), neurogenic itch (which is caused by systemic disorders), neuropathic itch (which is due to a primary neurological disorder) and psychogenic itch.

Prurigo nodularis

A skin condition that is characterized by itchy nodules (circumscribed, solid elevations on the skin), which usually appear on the arms or legs.

Pruritogens

Agents that induce itch by stimulating pruritoceptive sensory afferent neurons. In the skin, they are synthesized by and released from multiple non-neuronal cell types and include histamine, acids, ATP, prostaglandins and pro-inflammatory interleukins.

Alopecia

A type of pathological hair loss that mostly affects the scalp. The most common forms of alopecia are alopecia universalis, alopecia areata and alopecia androgenetica. Telogen Effluvium, which is characterized by diffuse hair shedding, is a form of alopecia.

Hirsutism

Excessive and increased hair growth (especially in women) on regions of the body where the occurrence of hair normally is minimal or absent.

Dermatitis

A universal term describing inflammation of the skin. It can be induced by various factors such as allergens (allergic dermatitis), infections, eczema (atopic dermatitis) or external compounds (contact dermatitis).

Apnoea

Prolonged periods of time without respiratory flow. Although humans can perform this manoeuvre voluntarily (by holding their breath), reflex apnoeas can be induced in human volunteers and animals by irritant stimulation of the respiratory tract.

Hair cycle

A life-long regeneration programme of the hair follicles that can be divided into three phases: anagen (growth), catagen (apoptosis-driven regression or involution) and telogen (resting or quiescence, preparation for the next anagen phase). This cycle is controlled by promoters (for example, insulin-like growth factor 1 and hepatocyte growth factor) and inhibitors (for example, interleukin-1β, and transforming growth factor-β2)

Respiratory irritation

A stereotypical reflex reduction in respiratory rate exhibited by small laboratory animals following irritant aerosol provocation. This behaviour generally predicts the irritation threshold for molecules in humans.

Pilosebaceous unit

Consists of the hair shaft, the hair follicle, the sebaceous gland and the erector pili muscle; causes the hair to stand up when it contracts.

Sebum

A lipid-enriched, oily exocrine product of the sebaceous glands that has various functions including waterproof barrier formation, antimicrobial activity, transport and thermoregulation.

Basal cell carcinoma

The most common type of malignant skin tumour, which develops from the basal cell layer of the epidermis. It rarely metastasizes, but without treatment it may cause substantial destruction by invading the deeper skin tissues.

Darier's disease

A congenital skin condition that is characterized by dyskeratosis (abnormal keratinization of the epidermis) and the appearance of pruritic, greasy and scaly skin papules (circumscribed, solid elevations on the skin) and plaques (confluences of papules).

Vitiligo

A skin disorder that is characterized by depigmentation of patches of skin. It develops as a result of impaired functions or death of skin melanocytes, which can be induced by various factors, such as autoimmune conditions, genetic factors, oxidative stress and infections.

Penh (enhanced pause)

A derived value that is supposed to characterize the ventilatory activity of freely moving rodents in plethysmography chambers where airflow is measured. Interpretation of this measurement is debated within the respiratory field.

Bronchoalveolar lavage

A procedure in which inflammatory cells and other materials within the airway lumen are collected via repeated washings.

Alveoli

Distal regions of the lung in which a thin barrier between airspaces and capillaries allows for gas exchange.

Filtration coefficient (Kf)

A measurement that is used to reflect the permeability of the pulmonary vasculature to fluid.

Autosomal dominant brachyolmia

A disorder that is typified by short stature, a short trunk and curved spine.

Spondylometaphyseal dysplasia

A skeletal disorder that is typified by short stature and abnormalities in the vertebrae and tubular bones.

Charcot–Marie–Tooth disease

Also known as hereditary motor and sensory neuropathy. This disease, named after the three doctors who first identified it, is one of the most common inherited neuropathies. Symptoms include weakness, motor atrophy and foot deformities.

Focal segmental glomerulosclerosis

A disease that is typified by glomerular scarring, which results in proteinuria, oedema and the eventual need for dialysis.

Familial episodic pain syndrome

A rare disorder that is typified by periods of severe pain in the trunk and upper body. Episodes are typically triggered by cold temperatures and/or a low energy state brought about by hunger or fatigue.

Mucolipidosis type IV

A lysosomal storage disorder. Symptoms typically present during the first year of life and affected individuals suffer from psychomotor retardation, ophthalmological abnormalities and anaemia.

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Moran, M., McAlexander, M., Bíró, T. et al. Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov 10, 601–620 (2011). https://doi.org/10.1038/nrd3456

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