Creatine and its phospho-creatine form play an important role maintaining ATP levels during high energy cellular activity and metabolism. In humans, creatine deficiency syndromes are characterized by moderate to severe mental retardation, speech and language delays, epilepsy and autistic behavior. Mutations in genes encoding the creatine biosynthetic enzymes as well as in the creatine transporter underlie many creatine deficiency disorders but the molecular and cellular mechanisms by which creatine deficiency leads to such prominent brain defects remain elusive. While conducting a genetic screen in C. elegans to identify genes that function redundantly with phosopholipase Cp, we isolated an allele of snf-3, which encodes a NaVCI"""""""" dependent neurotransmitter transporter with high sequence similarity to the mammalian creatine transporter. We hypothesize that phosphoinositol and creatine transporter signaling pathways converge to regulate [Ca2""""""""], homeostasis (oscillation) required for a nematode ultradian behavior, its defecation cycle. We will test this using genetic methods in combination with calcium and IP3 imaging as well as electrophysiological and biochemical techniques.
In aim 1, we propose to characterize the biochemical properties of SNF-3 and its subcellular localization and function in vivo.
In aim 2, we will determine a role for SNF-3 in phospholipase signaling. Lastly, we will characterize the role of SNF-3 in [Ca2+], homeostasis. Recent discoveries highlight the importance of creatine in brain health. Patients with creatine deficiency syndromes have severe neurological disorders and creatine supplementation protects the brain of patients with stroke and neurological syndromes. We propose that C. elegans defecation cycle represents a powerful model system to analyze the molecular and cellular biology of the creatine transporter. ? ? ?
| Peden, Aude S; Mac, Patrick; Fei, You-Jun et al. (2013) Betaine acts on a ligand-gated ion channel in the nervous system of the nematode C. elegans. Nat Neurosci 16:1794-801 |
