Ion channels in dry eye disease

Abstract

Dry eye disease (DED) which affects millions of people worldwide is an ocular surface disease that is strongly associated with pain, discomfort, and visual disturbances. Altered tear film dynamics, hyperosmolarity, ocular surface inflammation, and neurosensory abnormalities are the key contributors to DED pathogenesis. The presence of discordance between signs and symptoms of DED in patients and refractoriness to current therapies in some patients underpin the need for studying additional contributors that can be modulated. The presence of electrolytes or ions including sodium, potassium, chloride, bicarbonate, calcium, and magnesium in the tear fluid and ocular surface cells contribute to ocular surface homeostasis. Ionic or electrolyte imbalance and osmotic imbalance have been observed in DED and feed-forward interaction between ionic imbalances and inflammation alter cellular processes in the ocular surface resulting in DED. Ionic balances in various cellular and intercellular compartments are maintained by dynamic transport via ion channel proteins present in cell membranes. Hence, alterations in the expression and/or activity of about 33 types of ion channels that belong to voltage-gated channels, ligand-gated channels, mechanosensitive ion channel, aquaporins, chloride ion channel, sodium-potassium-chloride pumps or cotransporters have been investigated in the context of ocular surface health and DED in animal and/or human subjects. An increase in the expression or activity of TRPA1, TRPV1, Nav1.8, KCNJ6, ASIC1, ASIC3, P2X, P2Y, and NMDA receptor have been implicated in DED pathogenesis, whereas an increase in the expression or activity of TRPM8, GABA_A receptor, CFTR, and NKA have been associated with resolution of DED.

Keywords: Dry eye disease; electrolytes; ion channels; ions; transient receptor potential.

Figure 1

Ionic imbalance and dry eye disease. Schematic represents the feed-forward interaction or cycle between ionic or electrolyte imbalance and inflammatory processes that prevail. Ionic imbalance influences the synthesis, structural stability, activity and transport of certain proteins that are crucial in inflammatory processes. On the other hand, inflammation induces ionic imbalances by interfering with the transport and reabsorption of ions in the various cells and tissues, which results in cellular dysfunction that can amplify the inflammatory events in the cells and tissues. Ionic imbalance and inflammatory factors by themselves are well known to contribute toward dry eye disease (DED) signs and symptoms by (i) altering tear film stability, (ii) altering ocular surface epithelial cells’ functions including barrier integrity, mucin production, etc., and (iii) altering the excitability of sensory neurons, resulting in hyperalgesia or allodynia

Figure 2

Ion channels in ocular surface and dry eye disease. Schematic lists out the various ion channels that have been investigated in the context of ocular surface health and DED in animal and/or human subjects. Ion channels that belong to voltage-gated channels, ligand-gated channels, mechanosensitive ion channel, aquaporins, chloride ion channel, and sodium–potassium–chloride pumps and cotransporters. The ion channels that have been shown to contribute toward the induction of dry eye disease features are indicated with red arrow; ion channels that have been reported to contribute toward the resolution of dry eye disease features are indicated with a blue arrow. Ion channels indicated using black arrows are reported not vary in dry eye disease, or they are yet to be investigated in the context of dry eye disease