Many cells are covered with mysterious large holes, pores that have been associated with the sense of taste as well as Alzheimer’s disease, depression, and even asthma. Knowing the structure of these varied holes will help researchers better understand this range of associations and provide a blueprint for developing new therapies. As described recently in Nature Structural & Molecular Biology, researchers from professor Furukawa’s lab at the Cold Spring Harbor Laboratory showcased the detailed structure of two CALHMs and how they function. Professor Furukawa, played with words: “One of the most recently discovered of these ‘large holes’ are called calcium homeostasis modulators (CALHMs). They’re basically pores on the surface of some cells such as neurons, that let various molecules enter and exit the cell. If you have large holes in cells, you’d think the cells would burst open or shrink, yet cells with functioning pores remain quite happily as they are”. That suggests these pores are involved in maintaining cellular health.
To investigate this, the researchers studied two kinds of pores. CALHM1 is a non-selective, weakly voltage gated Ca2+ permeable ion channel that shares structural features with other intercellular proteins, known as connexins and pannexins The pore of CALHM1 is ~14 Å wide, similar to that of connexins: it is activated in part by membrane depolarization and by decreases in extracellular Ca2+ concentration. Originally discovered in an Alzheimer’s disease paradigm CALHM1 plays a role in cortical neuron excitability as well as in tongue taste perception. Mice that lack the Calhm1 gene show no avoidance of bitter compounds and no preference for sweet and umami. This pore is also involved in controlling the airways in lungs, which implicates it in asthma. Additionally, mutations in the genes that shape CALHM1 have been associated with Alzheimer’s disease. The CALHM1 channel has unusual ion selectivity and gating regulation properties. It is Ca2+ permeable, with a modest selectivity for Ca2+ over monovalent cations.
In addition, it demonstrates little selectivity even between monovalent cations and chloride. Thus, when CALHM1 is activated, the current carried through the channel is a mixture of Na+, K+, Cl−, and Ca2+, and its activation is predicted to be a depolarizing, excitatory influence on membrane properties. The researchers also studied another pore, CALHM2 that might be involved in depression. To their surprise, they found that CALHM2 has much larger pore size compared to CALHM1. Researchers think that presumably the opening and closing of these pores is somehow tightly regulated. This opening and closing might be key to how the pores influence taste or are associated with disease. To make sense of this, scientists first have to be able to visualize them before to proceed for further experiments. To visualize the structure of CALHM1 and CALHM2, the team used cryo-electron microscopy, which fires a powerful electron beam through a rapidly frozen specimen to obtain images.
They then carefully compound the images in various orientations into a 3D model that highlights the finite details of each pore’s structure. Professor Furukawa concluded with purposes and hopes: “We’ve provided science with the first blueprint of these pores to design therapeutic compounds. The hope is that such compounds could be effective in treating diseases and disorders like Alzheimer’s, depression and potentially in asthma”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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