Pannexins are a family of proteins found within cells that serve as channels or pores in the cell membrane. These channels facilitate the passage of small molecules, such as ions and metabolites, between the cell’s interior and its external environment. This function allows pannexins to participate in various cellular communication processes and biological activities.
Understanding Pannexins
Pannexins are transmembrane proteins, meaning they span the cell’s outer boundary. Three primary types are identified in chordates: Pannexin 1 (Panx1), Pannexin 2 (Panx2), and Pannexin 3 (Panx3). Panx1 is widely distributed throughout the body, found in numerous cells and organs, including the brain, heart, and immune cells.
Panx2 is primarily expressed in the central nervous system, while Panx3 is involved in bone and cartilage development. These proteins assemble to form channels in the cell membrane, enabling the movement of molecules such as adenosine triphosphate (ATP), calcium ions (Ca²⁺), and inositol triphosphate (IP3). These channels primarily connect the intracellular and extracellular spaces, rather than forming direct connections between adjacent cells.
Pannexins in Normal Cell Function
Pannexins play diverse roles in maintaining healthy cells and tissues. A significant function involves the controlled release of ATP, a molecule that acts as a signaling agent outside the cell. This ATP release is relevant in purinergic signaling pathways.
Pannexins also influence the regulation of inflammation and immune responses. For instance, Panx1-mediated ATP release from dying cells acts as a “find-me” signal, attracting immune cells like macrophages to clear cellular debris. In the nervous system, pannexins contribute to neural communication, including sensory processing and the propagation of calcium waves.
Pannexins and Disease
Dysregulation or altered function of pannexins can contribute to a range of pathological conditions. In chronic inflammation, Panx1-mediated ATP release can activate inflammasomes, leading to the production of pro-inflammatory cytokines such as interleukin-1β. This process can amplify inflammatory responses in various organs.
Pannexins are also implicated in neurodegenerative disorders like Alzheimer’s and Parkinson’s diseases. Overactivation of Panx1 channels can lead to activation of inflammasomes in neurons and glial cells, contributing to neuronal death. In ischemic injuries, Panx1 channels can exacerbate damage by contributing to calcium dysregulation, mitochondrial dysfunction, and the release of inflammatory molecules.
Certain types of cancer also show altered pannexin activity. Truncating mutations in Panx1 have been linked to the promotion of breast and colon cancer metastasis by enabling cancer cells to survive mechanical stress in the microcirculation through ATP release. Upregulated Panx1 proteins are observed in many cancer cells, and inhibiting Panx1 has been shown to reduce melanoma cell growth and migration.
Targeting Pannexins
The involvement of pannexins in numerous diseases makes them potential targets for therapeutic interventions. Research efforts are exploring ways to modulate pannexin activity using inhibitors. Over 30 inhibitors have been identified, including general gap junction blockers and mimetic peptides.
For example, probenecid, a drug used to treat gout, can inhibit Panx1 channels. Carbenoxolone (CBX) is another compound that inhibits Panx1 and has shown protective effects in various ischemic injuries and can mitigate cancer metastasis. Challenges remain in developing highly selective and stable pannexin-targeting drugs, as many current inhibitors also affect other channels or cellular processes.