A family of proteins known as Leucine-rich repeat-containing 8, or LRRC8, forms channels on the cell surface. These proteins are found in all vertebrate cells and act as gatekeepers, controlling the passage of substances in and out of the cell. This regulation is a fundamental aspect of cellular function, enabling cells to survive and communicate effectively with their surroundings.
The LRRC8 Protein Family
The term “LRRC8” refers to a family of five distinct proteins: LRRC8A, LRRC8B, LRRC8C, LRRC8D, and LRRC8E. These proteins assemble into a six-part channel that embeds within the cell’s membrane. The LRRC8A subunit is a required component for any functional channel to form, as the other subunits cannot create a working channel without it.
The remaining four members (LRRC8B, C, D, and E) are variable components that co-assemble with LRRC8A. The specific combination of these variable subunits dictates the channel’s unique properties and functions. This modular design allows for a wide range of channel behaviors. For example, a channel containing the LRRC8D subunit has different permeability characteristics than one containing LRRC8E.
Regulating Cell Size and Shape
One of the most well-documented functions of LRRC8 channels is the regulation of cell volume. Cells must maintain a relatively constant size and shape to function properly. They exist in an aqueous environment and are subject to osmotic pressure, where water moves across the cell membrane to balance the concentration of dissolved substances, or solutes, inside and out. If a cell takes in too much water, it can swell and potentially burst.
To counteract this, LRRC8 channels, also known as Volume-Regulated Anion Channels (VRACs), activate in response to cell swelling. This activation is thought to be triggered by the dilution of the cell’s internal contents, specifically a decrease in ionic strength. Once opened, these channels provide an exit route for negatively charged ions, primarily chloride, and small organic molecules called osmolytes.
The efflux of these particles increases the solute concentration outside the cell relative to the inside. Water then naturally follows these osmolytes out of the cell, a process called regulatory volume decrease (RVD). This movement of water reduces the cell’s internal volume, returning it to its normal size and preventing damage that would result from excessive swelling.
Transporting Cellular Messengers and Drugs
Beyond managing cell volume, LRRC8 channels transport a diverse array of larger molecules for cellular communication and therapy. This function is distinct from the release of ions for osmotic balance and depends on the channel’s specific subunit composition, as different combinations create pores with varying selectivity.
These channels can transport key neurotransmitters, including glutamate, aspartate, and GABA. The release of these signaling molecules from cells like astrocytes in the brain can influence neuronal activity, highlighting a role for LRRC8 channels in nervous system function. Furthermore, they transport other important signaling molecules like ATP, which can act as a messenger between cells.
This transport function extends to therapeutic agents. Certain chemotherapy drugs, such as cisplatin and carboplatin, rely on LRRC8 channels to enter cancer cells. Specifically, channels that include the LRRC8D subunit are particularly effective at transporting these drugs. This capability shows the channels can facilitate the uptake of substances as well as their release.
Connection to Disease and Treatment
The diverse functions of LRRC8 channels directly link them to a range of human health conditions and medical treatments. Because these channels are involved in fundamental cellular processes, their malfunction can have significant consequences.
In the immune system, mutations in the LRRC8A gene, which codes for the required channel subunit, can lead to an immunodeficiency called agammaglobulinemia. This condition is characterized by a failure of B-cells, the immune cells responsible for producing antibodies, to develop properly. The absence of functional LRRC8A channels halts the maturation process, leaving individuals unable to mount an effective antibody response to infections.
In the context of cancer, the expression levels of LRRC8 channels can influence the effectiveness of chemotherapy. As these channels are a primary route for platinum-based drugs like cisplatin and carboplatin to enter tumor cells, their abundance is a factor in treatment success. High expression of LRRC8A and LRRC8D can lead to greater drug accumulation inside the cancer cell, promoting cell death. Conversely, low expression can contribute to drug resistance, as the cancerous cells are less able to take up the therapeutic agent.
Emerging research also connects LRRC8 channels to other conditions. In the brain, these channels are implicated in the cellular swelling that occurs following a stroke, which can exacerbate tissue damage. There is also growing evidence for their involvement in metabolic health, particularly in the regulation of insulin secretion from pancreatic beta-cells and the development of adipocytes, or fat cells, which has implications for diabetes and obesity.