2012/06/18 by Zhongming Ma, Adam P. Siebert, King‐Ho Cheung +6 · 2 citations
Biochemistry, Genetics and Molecular Biology · Neuroscience · Chemistry · #Ion channel regulation and function #Ion Channels and Receptors #Neuroscience and Neuropharmacology Research #Extracellular #Homeostasis #Biophysics #Chemistry #Voltage-dependent calcium channel #Calcium #Cell biology #Ion channel #Depolarization #Membrane potential #Cav1.2 #Calcium metabolism #Biochemistry #Biology #Receptor
paper · pdf · doi:10.1073/pnas.1204023109
openalex publication_date 2012/06/18 · openalex created_date 2016/06/24 · openalex updated_date 2026/08/01
Extracellular Ca(2+) (Ca(2+)(o)) plays important roles in physiology. Changes of Ca(2+)(o) concentration ([Ca(2+)](o)) have been observed to modulate neuronal excitability in various physiological and pathophysiological settings, but the mechanisms by which neurons detect [Ca(2+)](o) are not fully understood. Calcium homeostasis modulator 1 (CALHM1) expression was shown to induce cation currents in cells and elevate cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) in response to removal of Ca(2+)(o) and its subsequent addback. However, it is unknown whether CALHM1 is a pore-forming ion channel or modulates endogenous ion channels. Here we identify CALHM1 as the pore-forming subunit of a plasma membrane Ca(2+)-permeable ion channel with distinct ion permeability properties and unique coupled allosteric gating regulation by voltage and [Ca(2+)](o). Furthermore, we show that CALHM1 is expressed in mouse cortical neurons that respond to reducing [Ca(2+)](o) with enhanced conductance and action potential firing and strongly elevated [Ca(2+)](i) upon Ca(2+)(o) removal and its addback. In contrast, these responses are strongly muted in neurons from mice with CALHM1 genetically deleted. These results demonstrate that CALHM1 is an evolutionarily conserved ion channel family that detects membrane voltage and extracellular Ca(2+) levels and plays a role in cortical neuronal excitability and Ca(2+) homeostasis, particularly in response to lowering [Ca(2+)](o) and its restoration to normal levels.