The enigma of store-operated Ca2+-entry in neurons: answers from the Drosophila flight circuit

Abstract

In neurons a well-defined source of signaling Ca2+ is the extracellular medium. However, as in all metazoan cells, Ca2+ is also stored in endoplasmic reticular compartments inside neurons. The relevance of these stores in neuronal function has been debatable. The Orai gene encodes a channel that helps refill these stores from the extracellular medium in non-excitable cells through a process called store-operated Ca2+ entry or SOCE. Recent findings have shown that raising the level of Orai or its activator STIM, and consequently SOCE in neurons, can restore flight to varying extents to Drosophila mutants for an intracellular Ca2+-release channel – the inositol 1,4,5-trisphosphate receptor (InsP3R). Both intracellular Ca2+-release and SOCE appear to function in neuro-modulatory domains of the flight circuit during development and acute flight. These findings raise exciting new possibilities for the role of SOCE in vertebrate motor circuit function and the treatment of neurodegenerative disorders where intracellular Ca2+ signaling has been implicated as causative.

Neuronal Store-Operated Calcium Entry Pathway as a Novel Therapeutic Target for Huntington's Disease Treatment

“…The molecular composition of neuronal SOC pathway is poorly understood, with potential components including members of mammalian Trp family and Orai1 channels (Berna-Erro et al, 2009; Gruszczynska-Biegala et al, 2011; Hasan and Venkiteswaran, 2010; Putney, 2003; Venkiteswaran and Hasan, 2009). Our electrophysiological measurements indicate that the channels upregulated in SK-N-SH cells in response to Htt-138Q transfection are relatively non-selective (Fig 4B), consistent with the known properties of mammalian TRPC channels (Montell, 2005).…”

“…The importance of store-operated Ca 2+ entry (SOC) pathway in neuronal function is poorly understood (Hasan and Venkiteswaran, 2010; Putney, 2003). However, potential role of neuronal SOC pathway in pathological conditions has been suggested based on studies with experimental models of AD (Herms et al, 2003; Leissring et al, 2000; Yamamoto et al, 2007; Yoo et al, 2000), PD (Bollimuntha et al, 2005; Selvaraj et al, 2009b), cerebral ischemia (Berna-Erro et al, 2009) and excititoxicity (Narayanan et al, 2008).…”

“…It has been previously suggested that these compounds do not inhibit NF-κB directly but act by blocking store-operated calcium (Ca 2+ ) entry (SOC) (Choi et al, 2006), a critical step upstream of NF-κB activation in immune cells. An importance of SOC pathway for neuronal physiology was highlighted in recent studies of STIM2 knockout mice (Berna-Erro et al, 2009), genetic studies in Drosophila (Hasan and Venkiteswaran, 2010; Venkiteswaran and Hasan, 2009) and in recent functional studies with neuronal cultures (Gruszczynska-Biegala et al, 2011). In our studies we evaluated activity of isolated compounds as SOC inhibitors in HD neurons and validated their neuroprotective effects in experiments with MSN cultures from YAC128 transgenic mice.…”

Synaptic Activity in Serotonergic Neurons Is Required for Air-Puff Stimulated Flight in Drosophila melanogaster

“…The importance of aminergic neurons in Drosophila air-puff stimulated flight has been shown previously in the context of IP 3 R signaling and SOCE [8], [30]. However, these data are not straightforward.…”

Store-operated calcium entry into SK-N-SH human neuroblastoma cells modeling huntington’s disease

“…Molecular structures of channels responsible for store operated calcium entry are insufficiently studied in nerve cells; however, a list of proteins potentially involved in the process includes TRPC and Orai1 [25][26][27]. Channels composed of Orai1 exhibit high reversal potential and inward recti fication, whereas TRPC channels are rather non selective [12].…”