TMCO1 Is an ER Ca 2+ Load-Activated Ca 2+ Channel

Abstract

Maintaining homeostasis of Ca(2+) stores in the endoplasmic reticulum (ER) is crucial for proper Ca(2+) signaling and key cellular functions. The Ca(2+)-release-activated Ca(2+) (CRAC) channel is responsible for Ca(2+) influx and refilling after store depletion, but how cells cope with excess Ca(2+) when ER stores are overloaded is unclear. We show that TMCO1 is an ER transmembrane protein that actively prevents Ca(2+) stores from overfilling, acting as what we term a "Ca(2+) load-activated Ca(2+) channel" or "CLAC" channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca(2+) overloading and disassembly upon Ca(2+) depletion and forms a Ca(2+)-selective ion channel on giant liposomes. TMCO1 knockout mice reproduce the main clinical features of human cerebrofaciothoracic (CFT) dysplasia spectrum, a developmental disorder linked to TMCO1 dysfunction, and exhibit severe mishandling of ER Ca(2+) in cells. Our findings indicate that TMCO1 provides a protective mechanism to prevent overfilling of ER stores with Ca(2+) ions.

Calcium at the Center of Cell Signaling: Interplay between Endoplasmic Reticulum, Mitochondria, and Lysosomes

“…Of note, although the cytoplasmic domain of RyR is much larger than the one of InsP 3 R, the location of N-terminal regions, required for the formation of functional tetramers, relative to the transmembrane channel regions of the receptors, is very similar. A novel ER Ca 2+ channel has been identified to be encoded by the TMCO1 gene (Transmembrane and coiled-coil domains 1) [13]. At physiological [Ca 2+ ] TMCO1 is present as inactive monomers in the ER membrane.…”

“…Above a certain [Ca 2+ ] threshold, TMCO1 monomers form active tetrameric channels, which extrude Ca 2+ form the ER matrix, thus preventing ER Ca 2+ overload. Mutations in the TMCO1 gene are associated to human cerebrofaciothoracic (CFT) dysplasia spectrum, which is mainly characterized by craniofacial dysmorphism, skeletal anomalies, mental retardation and ataxia [13]. …”

The hills and valleys of calcium signaling

“…The cloning of the major component of mitochondrial uniporter (Baughman et al, 2011;De Stefani et al, 2011) has been revolutionizing studies on mitochondrial Ca 2+ uptake, although other uptake mechanisms may also exist (Feng et al, 2013). More recently, a novel Ca 2+ release channel on the ER membrane, TMCO1, which helps relief ER stores from Ca 2+ overload, has been described (Wang et al, 2016). Thus, new players are emerging for the moment-to-moment regulation of Ca 2+ contents both in the cytosol and at the luminal side of intracellular organelles.…”

“…This conference series, which has pretty much kept its original name and general themes, has continued at two to three year intervals in different places of the world for the next forty some years. , Yan et al, 2015Ge et al, 2015;Wang et al, 2016). The Ca 2+ Signaling meetings, therefore, not only provide an important platform for networking and information exchange but also offer the opportunity to celebrate the recent success.…”

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

“…Their contributions to the pathogenesis of glaucoma are still unclear; however, basic functionalities have been established. TMCO1 encodes a transmembrane protein that functions as a calcium channel in response to excess calcium levels in the ER [28]. ABCA1 belongs to a family of transporters and functions as a cholesterol efflux pump, and GAS7 may promote maturation and differentiation of neurons.…”