Calcium Sensors in Neuronal Function and Dysfunction

Abstract

Calcium signaling in neurons as in other cell types can lead to varied changes in cellular function. Neuronal Ca 2+ signaling processes have also become adapted to modulate the function of specific pathways over a wide variety of time domains and these can have effects on, for example, axon outgrowth, neuronal survival, and changes in synaptic strength. Ca 2+ also plays a key role in synapses as the trigger for fast neurotransmitter release. Given its physiological importance, abnormalities in neuronal Ca 2+ signaling potentially underlie many different neurological and neurodegenerative diseases. The mechanisms by which changes in intracellular Ca 2+ concentration in neurons can bring about diverse responses is underpinned by the roles of ubiquitous or specialized neuronal Ca 2+ sensors. It has been established that synaptotagmins have key functions in neurotransmitter release, and, in addition to calmodulin, other families of EF-hand-containing neuronal Ca 2+ sensors, including the neuronal calcium sensor (NCS) and the calcium-binding protein (CaBP) families, play important physiological roles in neuronal Ca 2+ signaling. It has become increasingly apparent that these various Ca 2+ sensors may also be crucial for aspects of neuronal dysfunction and disease either indirectly or directly as a direct consequence of genetic variation or mutations. An understanding of the molecular basis for the regulation of the targets of the Ca 2+ sensors and the physiological roles of each protein in identified neurons may contribute to future approaches to the development of treatments for a variety of human neuronal disorders.C alcium signaling in many cell types can mediate a diverse range of changes in cellular function affecting gene expression, cell growth, development, survival, and cell death. In addition, neuronal calcium signaling processes have become adapted to modulate the function of other important pathways in the brain, including neuronal survival, axon outgrowth (Spitzer 2006), and changes in synaptic strength (Catterall and Few 2008;Catterall et al. 2013).Changes in the concentration of intracellular free Ca 2+ ([Ca 2+ ] i ) are essential for the transmission of information through the nervous system as the trigger for neurotransmitter release at synapses. In addition, alterations in [Ca 2+ ] i can lead to a wide variety of different physiological changes that can modify neuronal functions over a range of time domains of milliseconds through 10 sec, to minutes to days or longer (Berridge 1998). It has long been believed that

NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons

“…We found no evidence for transcriptional compensation of NCS-1 loss by KChip3. KChip3 (also named Calsenilin or DREAM) has overlapping functions with NCS-1 (Naranjo and Mellstrom, 2012; Burgoyne et al, 2019), and not only constitutes a beta subunit for Kv4.3 channels (An et al, 2000), that are involved in PD pathology (Subramaniam et al, 2014; Dragicevic et al, 2015), but it can also shuttle from the plasma-membrane to the nucleus, and act as a Ca 2+ dependent transcription repressor by direct DNA binding (Carrion et al, 1999; Mellstrom and Naranjo, 2001; Gomez-Villafuertes et al, 2005; Mellstrom et al, 2014).…”

“…Hence, intracellular Ca 2+ levels are tightly controlled (Gleichmann and Mattson, 2011; Heine et al, 2019). Neuronal Ca 2+ sensor proteins (NCS) respond to changes in intracellular Ca 2+ concentrations with conformational changes that allow them to bind diverse interaction partners, and to activate a variety of different signaling pathways (Burgoyne and Haynes, 2012; Choudhary et al, 2018; Burgoyne et al, 2019). The widely expressed neuronal Ca 2+ sensor NCS-1 (Pongs et al, 1993) modulates e.g., voltage-gated Ca 2+ channels (Cav) (Tsujimoto et al, 2002; Weiss et al, 2010), A-type K + channels (Nakamura et al, 2001; Guo et al, 2002), that are composed of Kv4 α- and KChip3 β-subunits in SN DA neurons (Liss et al, 2001), G-protein coupled receptor kinases (GRK), and G-protein coupled dopamine D2-receptors (Kabbani et al, 2002; Pandalaneni et al, 2015), to just name a few.…”

Molecular Targets for Combined Therapeutic Strategies to Limit Glioblastoma Cell Migration and Invasion

“…Very high transcript levels in glioblastoma (Table 1) were measured for synaptotagmin-11. Synaptotagmins generally are associated with evoked release of synaptic and secretory vesicles, as low affinity Ca 2+ sensors that can bind to syntaxin and SNAP-25 (Burgoyne et al, 2019). Synaptotagmin 11 (Syt11), a substrate for ubiquitinylation by parkin, is one of the risk genes for Parkinson's disease; overexpression (resulting from parkin dysfunction) leads to impaired dopamine release, degeneration of dopaminergic neurons, and associated motor behavioral deficits (Wang et al, 2018a).…”

A Novel Approach to Bacterial Expression and Purification of Myristoylated Forms of Neuronal Calcium Sensor Proteins

“…The elution was performed using (1) 20 mM Tris-HCl-buffer (pH 7.5), 2 mM MgCl 2 , 1 mM DTT and 1 mM EGTA and (2) deionized water. The bulk of the myristoylated proteins was eluted in step (1).…”

“…Neuronal calcium sensors (NCSs) are EF-hand Ca 2+ -binding proteins responsible for transduction of calcium signals into a wide range of neuronal responses by regulating activity of effector enzymes and other target proteins (for review, see [ 1 ]). Due to these properties, NCSs are involved in a number of processes crucial for neuronal function, including reception, neurotransmission, synaptic plasticity, neuronal growth and survival [ 2 , 3 , 4 , 5 , 6 , 7 ].…”