September 22, 2017 16:00 - 17:00
BSI Central Building 1F Seminar Room
Na, K-ATPase (NKA) is well known for its function as an ion pump. In collaboration with professor Mikoshiba we have demonstrated that NKA also acts as a signal transducer activated by ouabain. NKA interacts directly with the IP3 receptor to initiate a calcium oscillatory signal. Down-stream effects include protection from apoptosis, and tissue protective effect has been demonstrated in kidney and brain. In a recent phospho-proteomic study we found that the NKA/IP3R signaling pathway alters the state of phosphorylation of several calcium dependent proteins, including the IP3R, the calcium channel STIM, CAMKK1 and CAMK2.
NKA is the most energy consuming protein in the brain. Yet it is only recently, when NKA dysfunction has been demonstrated in both inherited and neurodegenerative diseases, that neuronal Na, K-ATPase has received the attention it deserves. Neurons express both the ubiquitous α1 catalytic subunit and the neuron specific α3 catalytic subunit, which has a lower sodium-affinity than α1. The relative distribution of α1 and α3 differs depending on brain region. Critical functions of neuronal Na, K-ATPase include maintenance of membrane potential, prompt restoration of intracellular sodium after neuronal activity and control of after-hyperpolarization. Loss of function results in reduced threshold for epileptic seizures, loss of gait control and neuronal death.
Mutation of the α3 subunit is associated with several diseases, including Rapid Onset Dystonia Parkinsonism (RDP) and Alternating Hemiplegia in Childhood. The manifestations of a common RDP mutation, T613M, expressed in a mouse model and a unique case of α1 mutation associated with catastrophic epilepsy will be discussed.
The α3 subunit has recently been demonstrated to be a preferential target for several pathological proteins associated with neurodegenerative diseases. α-Synuclein (α-syn) is the principal component of Lewy bodies, a hallmark of Parkinson disease. In a collaborative study with Antoine Triller, we showed that extracellular applied α-syn fibers and oligomers preferentially interact with α3, and that this results in impaired control of intracellular sodium and membrane potential and calcium toxicity.
- Open to Public
- Katsuhiko Mikoshiba [Katsuhiko Mikoshiba, Developmental Neurobiology ]
Name: Rinkei Okano