Mediating the early response to acute hypoxia

Neurons in the brain require a continuous supply of oxygen for normal activity. If the level of oxygen in the brain decreases—for example when a blood vessel becomes blocked—neurons begin to die, and permanent brain damage can result. A shortage of oxygen first causes sodium ion channels within the surface membrane of the neurons to open. Sodium ions then flow into the cells through these open channels to trigger a cascade of events inside the cells that ultimately results in their death.

In “SUMOylation of NaV1.2 channels mediates the early response to acute hypoxia in central neurons” (Elife), Plant et al. now reveal how oxygen deficiency, otherwise known as hypoxia, rapidly increases the flow of sodium ions into brain cells. By inducing hypoxia in neurons from rat brain, Plant et al. show that a lack of oxygen causes SUMOylation, a process whereby a series of enzymes work together to attach a Small Ubiquitin-like Modifier (or SUMO) protein, of specific sodium ion channels in under a minute. The channels linked to the SUMO protein, a subtype called Nav1.2, open more readily than unmodified channels, allowing more sodium ions to enter the neurons.

Plant et al. study granule cells of the cerebellum, the most numerous type of neuron in the human brain. Further investigation is required to determine if SUMOylation of Nav1.2 channels underlies the response of other neurons to hypoxia as well. It also remains to be discovered whether molecules that block the SUMOylation of Nav1.2 channels, or that prevent the flow of sodium ions through these channels, could reduce the number of brain cells that die in low-oxygen conditions such as stroke.

doi: 10.7554/eLife.20054.
SUMOylation of NaV1.2 channels mediates the early response to acute hypoxia in central neurons
Leigh D Plant, Jeremy D Marks, Steve AN Goldstein
eLife 2016;5:e20054

Methylgloxal and anxiety disorder

methylglyoxal, aka pryuvaldehyde

A recent paper in The Journal of Clinical Investigation by researchers from the University of Chicago, working together with Assistant Research Professor of Biochemistry Leigh Plant from Brandeis, reveals a new mechanism for anxiety disorders involving the metabolite methylglyoxal (MG) (right).  The researchers investigated the effect of Glyoxalase 1 (Glo1) expression in mice. Increasing Glo1 copy number, and hence expression, in mice increased anxiety-like behavior. Since Glo1 metabolizes MG, they looked for a direct effect by administering MG, and found it had an anxiolytic effect in the mouse model (n.b.. MG is toxic, so don’t take it to treat anxiety). Inhibitors of Glo1 might therefore have anxiolytic effects, which they showed for the inhibitor S-bromobenzylglutathione cyclopentyl diester

Electrophysiology experiments were conducted to elucidate the mechanism of action of MG, suggesting that it had a GABAergic effect in vivo, and specifically that it is an agonist of the GABAA receptor in multiple neuron types.

So why is a relatively reactive small molecule, normally considered a by-product of glycolysis in animals, acting at neuronal receptors? Can this be exploited with pharmacological methods? What other functions does methylglyoxal have in the nervous system?  It may have many — another very recent paper in Nature Medicine suggests a role for MG in pain sensitivity and diabetic neuropathy, so there may be many interesting parts to this story.

Pre-med undergraduates should take note — keeping track of all those metabolites in glycolysis that you learn about in introductory biochemistry is far from irrelevant to modern medicine!



SUMO Proteins Emerge as Critical K2P Channel Regulators

In memory of Dan Getz (1969-2006) and sponsored by the Dan Getz Endowed Fund for Heart Disease Research, the most recent lecture in the Heart Research Series was presented on Wednesday afternoon. For the many that were in attendance, Dr. Steve Goldstein, the newly appointed Provost of the university, presented a wonderful story on his ongoing research involving K2P channels. The ubiquitously expressed K2P channels are critical in regulating a cell’s resting membrane potential, making them essential for the proper function of any cell that operates through electrical stimulation. His research has uncovered the surprising result that the activity of these elusive channels is regulated by small ubiquitin-like modifier (SUMO) proteins. Sumoylation was widely thought to only occur in the nucleus, but a number of elegantly designed experiments proved that this is not the case. The recent finding that the activity of these channels is modulated by sumoylation uncovers an entirely new way of thinking about K2P channel activity. Although the research presented was focused on specific isoforms of the channel, Dr. Goldstein’s results will extend to aid research involved with trying to understand diseases of the heart and beyond.

Colocalization of SUMO1 and K2P1 at the plasma membrane, from Plant et al. PNAS 107(23): 10743–10748, 2010.

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