Could Dry Eye Be a Channelopathy?

Specializing in a relatively isolated organ system, optometry and ophthalmology are often seen as somewhat separate from other medical specialties, much like dentistry. While the eyes are certainly connected to broader health care fields such as rheumatology and neurology, eye care is usually managed in isolation, with less collaboration across other medical disciplines. In contrast, specialties such as cardiology and oncology often rely heavily on cross-specialty consultations to manage complex cases. In this sense, we are similar to dentists. In fact, in our stand-alone eye center, separate from the other outpatient specialties at the University of Colorado School of Medicine, our ophthalmology residents even joke that we are "eye dentists," a nickname that also inspired our fantasy football league.

For this reason, it seems plausible that concepts normalized to other specialties may seem foreign to us practitioners in eye care. One such concept includes channelopathies, which are defined as disorders caused by dysfunction of ion channels (protein channels that regulate the flow of ions such as sodium, potassium, calcium, and chloride across cell membranes).¹

CHANNELOPATHIES: A DEEP DIVE

Channelopathies are commonly recognized as contributing to diseases in fields such as neurology, cardiology, and neuromuscular medicine.¹ These “channels” refer to membrane-bound proteins that control the movement of ions into and out of cells. Ion channels are found on cell membranes of neurons, muscles, cardiac tissue, and epithelial cells.¹ Many different types of channels exist, including voltage-gated, ligand-gated, mechanosensitive, and leak channels.¹

Dysfunction of specific ion channels may instigate or influence disease states in many organ systems throughout the body.¹ In neurology, channelopathies are a frequent cause of epilepsy and other conditions such as migraines or muscle weakness.¹ In cardiology, channelopathies are a common cause of arrhythmias such as long QT syndrome and atrial fibrillation.¹ In pulmonology, they contribute to the development of cystic fibrosis.¹ In nephrology, channelopathies can lead to kidney dysfunction in conditions such as kidney stones or salt imbalances, such as Bartter syndrome.¹ In dermatology, channelopathies are associated with skin disorders such as eczema or psoriasis.¹

In the context of the eyes, retina specialists are perhaps more familiar with channelopathies, as genetic mutations in specific ion channels are known to contribute to conditions such as retinitis pigmentosa (eg, CNGB1), congenital stationary night blindness (eg, TRPM1, CACNA1F), and Leber congenital (eg, CEP290).^2-5 In these cases, medications are being developed to specifically target channel dysfunctions, and genetic testing is sometimes available to detect the specific channels involved in these pathologies.

THE ROLE OF ION CHANNELS & NOCICEPTORS

The concept of ion channels in dry eye disease (DED) is not frequently discussed but is likely to become more familiar to providers as treatments targeting ion channels on the corneal nerves are developed. The cornea houses three main types of nociceptors: polymodal nociceptors, mechano-nociceptors, and cold thermoreceptors.6 You can think of “nociceptors” as pain receptors or sensory neurons. A receptor on the corneal nerves that, when stimulated, leads to an action potential along the corneal nerves.

Polymodal nociceptors are associated with A and C nerve fibers, mechano-nociceptors are linked to A fibers only, and cold thermoreceptors involve both A and C fibers.^7,8 Each of these nociceptors plays a role in initiating nerve firing in response to different stimuli, which is critical for understanding pain and discomfort in conditions such as DED.⁹ A key player in this process is the transient receptor potential (TRP) channel, a family of ion channels involved in detecting various stimuli such as temperature, mechanical force, and chemical irritants.⁸ These channels are expressed on the corneal nerves and help mediate the sensory responses that lead to the sensations of pain and discomfort often associated with DED.^6,9

Polymodal Nociceptors

Polymodal nociceptors are responsible for detecting a broad range of stimuli, including mechanical touch, heat, chemical irritants, and osmolarity.^6,8 These nociceptors are associated with several ion channels, including TRPV1, TRPA1, Piezo2, and ASICs.⁶ Among these, TRPV1 is the predominant ion channel in polymodal nociceptors. When stimulated, TRPV1 plays a central role in driving the symptoms of DED.⁹ Overactivation of TRPV1 can lead to increased reflexive tearing, elevated inflammatory biomarkers, and peripheral sensitization of the corneal nerves, contributing to conditions such as corneal neuropathic pain.⁶ To address this, several companies are developing drugs aimed specifically at modulating the TRPV1 channel. For example, the TRPV1 antagonist libvatrep (Novartis) seeks to alleviate pain and discomfort by blocking TRPV1 activation.¹⁰ Tivanisiran (Sylentis), on the other hand, targets TRPV1 differently by inhibiting the synthesis of the TRPV1 ion channel itself, thus reducing stimulation by decreasing the number of available channels.¹¹

Mechano-Nociceptors

Mechano-nociceptors are responsible for detecting physical touch and pressure.^6,8 These nociceptors are activated with mechanical stimulation, such as during a corneal nerve sensation test or when a foreign body presents itself in the eye. They are primarily associated with Piezo2 ion channels, which play a key role in sensing mechanical forces and translating them into nerve signals.⁶ An example of mechano-nociceptor stimulation is trichiasis, where an eyelash contacts the cornea, causing pain.

Cold Thermoreceptors

Cold thermoreceptors are unique in that they do not primarily detect pain as other nociceptors do but instead are involved in sensing ocular surface wetness. These nociceptors detect relative cooling of the cornea as tears begin to evaporate or by sensing hyperosmolarity in the tear film.^8,12 This detection is mediated through the TRPM8 ion channel. When triggered, the TRPM8 channel signals the lacrimal gland to increase basal tear secretion.¹²

Acoltremon (Alcon), a TRPM8 agonist, is under development, with an expected FDA decision in May 2025. Unlike medications that aim to antagonize ion channels to reduce symptoms and inflammation, Acoltremon stimulates TRPM8, thereby increasing tear secretion to help restore tear film balance.¹³ A compelling argument for considering some cases of dry eye as a channelopathy is the fact that TRPM8 expression declines with age, potentially leading to an aqueous deficiency.^14,15 This type of drug could help restore tear film homeostasis in patients with diminished TRPM8 function. It is also possible that a drug like this could be helpful in treating sub-types of neuropathic ocular pain.¹⁶

BUILDING A STRONGER FOUNDATION FOR DRY EYE TREATMENT

It is important for practitioners to have a basic understanding of nociceptors and ion channels, as this knowledge helps us better interpret the symptoms our patients with DED may be experiencing. The term channelopathy is not often considered in eye care when treating dry eye; however, it is entirely possible that the over- or underexpression of specific corneal nerve ion channels could contribute to increased symptoms of ocular discomfort or impaired tear film homeostasis.

Beyond improving our understanding of symptomology, knowledge of the ion channels associated with nociceptors will better equip practitioners to make informed clinical decisions as targeted therapies for specific ion channels and nociceptors enter the market. With ongoing research into ion channel-targeting therapies, the future of dry eye management could shift toward more precise, individualized treatments that address the underlying molecular mechanisms, improving patient outcomes and quality of life.