Ion channels - sodium and potassium in the brain

[Bernard]

“The sodium channel opening at the beginning of a nerve impulse is like releasing a compressed spring,” Cooper explains. “Without other influences, there is a tendency to keep reverberating, leading to additional, unwanted nerve impulses.”

Potassium channels have a calming influence on the nerve. “Potassium channels work like shock absorbers, holding back sodium channel activity for a period after each nerve impulse,” Cooper continues. Indeed, some patients have mutations in potassium channels that decrease this control, causing excessive nerve firing manifested as epileptic seizures and uncontrolled muscle movements called myokymia and ataxia.

Ion Channel Interaction Sheds Light on Epilepsy, Other Neurological Disorders

[Bernard]

Protein's potential as a regulator of brain activity discovered

UCI study points to new therapeutic possibilities for epilepsy and neurodegenerative diseases

Irvine, Calif. -- UC Irvine researchers have found that a protein best known for building connections between nerve cells and muscle also plays a role in controlling brain cell activity. The finding points to possible therapeutic applications in the development of new drugs for treatment of epilepsy and neurodegenerative disorders.

Martin Smith, professor of anatomy and neurobiology in the School of Medicine, and his UCI colleagues discovered that agrin -- a protein that directs synapse formation between nerve and muscle cells -- can also inhibit the function of "pumps" that control sodium and potassium levels within cells.

These pumps, called sodium-potassium ATPases -- or sodium pumps, for short -- are especially important in electrically excitable cells, where they provide the basis for electrical impulses, known as action potentials, which are responsible for muscle contraction and signaling between nerve cells in the brain. They do this by pumping sodium out of a cell and pumping potassium in, setting up an electrochemical gradient -- in a sense, turning the cell into a battery.

If this activity isn't properly moderated, uncontrollable electrical impulses can be triggered, which is one of the cellular mechanisms behind an epileptic seizure, for instance.

This is where agrin comes into action. The UCI researchers observed in laboratory tests that agrin controls the excitability of nerve cells in the brain by regulating sodium pump activity. Adding agrin caused nerve cells to fire electrical impulses uncontrollably. In turn, the researchers found that they could block these electrical impulses by introducing small fragments of agrin, which prevented the full agrin proteins from binding their sites on the sodium pump molecules and initiating action potentials.

"The ability of agrin to modulate nerve cell excitability suggests that the agrin-sodium pump interactions can be exploited as a novel therapeutic target for epilepsy and other brain disorders," Smith said.

Agrin proteins are also expressed in heart tissue, and Smith notes that sodium pump inhibitors, such as digoxin, are commonly used to treat congestive heart failure. Agrin may, therefore, have therapeutic value for the treatment of diseases affecting tissues and organs outside of the brain.

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The study appears in the April 21 issue of Cell. Lutz Hilgenberg, Hailing Su, Huaiyu Gu and Diane O'Dowd of UCI collaborated on the study, which was supported by the National Institutes of Health.

UCI has filed for patents covering the use of agrin and its derivatives in treatment of epilepsy and other pathologies of the brain and as tools that could be used to screen for novel compounds that regulate sodium pump activity.

Protein's potential as a regulator of brain activity discovered

[RobinN]

The synaptic serine protease neurotrypsin is considered to be essential for the establishment and maintenance of cognitive brain functions, because humans lacking functional neurotrypsin suffer from severe mental retardation. Neurotrypsin cleaves agrin at two homologous sites, liberating a 90-kDa and a C-terminal 22-kDa fragment from the N-terminal moiety of agrin. Morphological analyses indicate that neurotrypsin is contained in presynaptic terminals and externalized in association with synaptic activity, while agrin is localized to the extracellular space at or in the vicinity of the synapse. Here, we present a detailed biochemical analysis of neurotrypsin-mediated agrin cleavage in the murine brain. In brain homogenates, we found that neurotrypsin exclusively cleaves glycanated variants of agrin. Studies with isolated synaptosomes obtained by subcellular fractionation from brains of wild-type and neurotrypsin-overexpressing mice revealed that neurotrypsin-dependent cleavage of agrin was concentrated at synapses, where the most heavily glycanated variants of agrin predominate. Because agrin has been shown to play an important role in the formation and the maintenance of excitatory synapses in the central nervous system, its local cleavage at the synapse implicates the neurotrypsin/agrin system in the regulation of adaptive reorganizations of the synaptic circuitry in the context of cognitive functions, such as learning and memory.

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