including muscle contraction, transcription, cell division, and synaptic vesicle release. Paradoxically, calcium can also trigger cell death and cellular necrosis. Therefore, dysregulation in calcium regulation can affect cells in different ways and to varying degrees. Consequently, the levels of calcium need to be tightly regulated. Indeed, defective calcium signaling has been implicated in many neurodegenerative diseases, muscular dystrophies and heart disease. To understand the regulation of calcium signaling, we have established a novel system to identify gene products involved in the regulation and response to cytosolic calcium levels. Furthermore, we have developed a novel preparation to measure calcium dynamics in vivo. Previously, we found that VAV-1, a highly evolutionarily conserved guanine nucleotide exchange factor for the Rho Family GTPases, regulates several rhythmic behaviors in Caenorhabditis elegans by modulating calcium oscillations. These rhythmic behaviors include pharyngeal pumping, ovulation and fertilization, and defecation. To understand the mechanism(s) VAV-1 utilizes to regulate calcium oscillations and these rhythmic behaviors, we have used the power of C. elegans genetics to identify other potential regulators of calcium. Our analyses thus far have found evidence that VAV-1 modulates the release of calcium from intracellular stores to regulate cytosolic calcium levels. In order to elucidate the mechanisms underlying VAV-1's control of calcium signaling and rhythmic behavior, we are taking a multifaceted approach, which involves in vivo calcium imaging in concert with genetic, molecular and cell biology techniques to explore VAV-1 dependent regulation of calcium signaling. Since there are many similarities between vertebrate and invertebrate signaling cascades and evidence points to their commonality at the molecular, structural and functional level, the goals of this proposal will aid in understanding the in vivo mechanisms involved in calcium signaling.
The regulation of calcium signaling is of paramount importance to many fields, including cardiac and skeletal muscle contraction, synaptic activity, learning and memory, excitotoxicity and cellular necrosis, and aging. Our long-term goals are to resolve the mechanisms that cells use to regulate and decipher calcium signaling using genetic, molecular and cell biological methods.
|Fry, Amanda L; Laboy, Jocelyn T; Norman, Kenneth R (2014) VAV-1 acts in a single interneuron to inhibit motor circuit activity in Caenorhabditis elegans. Nat Commun 5:5579|