Graded regulation of the Kv2.1 potassium channel

via Coturnix: This is exciting for two reasons: 1) changing persepctive to seeing things in a graded, variable continuum rather than just viewing things as an on/off, either/or switch, and 2) using #1 to be able to apply it to produce possibly groundbreaking work to address complexities of how even single neurons—-not to mention an entire brain—- may function:

“We’ve shown that brains cells regulate activity in an incremental way, with thousands of different possible levels of activity,” explained James Trimmer, senior author of the paper and professor of medical pharmacology and toxicology at UC Davis School of Medicine. He and his colleagues studied an ion channel that controls neuronal activity called Kv2.1, a type of voltage-gated potassium channel that is found in every neuron of the nervous system.

“Our work showed that this channel can exist in millions of different functional states, giving the cell the ability to dial its activity up or down depending on the what’s going on in the external environment,” said Trimmer. This regulatory phenomenon is called ‘homeostatic plasticity’ and it refers, in this case, to the channel protein’s ability to change its function in order to maintain optimal electrical activity in the neuron in the face of large changes within the brain or the animal’s environment. “It’s an elegant feedback system,” he added.

[snip] The current study is the first to combine mass spectrometry-based proteomics and ion channel biophysics to the study of living brain cells. “This is an important biological question that couldn’t have been answered any other way,” Trimmer said.

Most cells in the body can get by with on/off-like switches, allowing them grow and proliferate when needed. In fact, examples of these ‘switches’ include the well-studied products of oncogenes, proteins that get stuck in the ‘on’ position and cause cancer. Brain cells, however, must multi-task, receiving and processing signals from various sources, both inside and outside the body. “This ability to deal with a variety of signals involves some fairly sophisticated and subtle regulation of neuronal activity,” Trimmer said.

The original article is called Graded regulation of the Kv2.1 potassium channel by variable phosphorylation (Park KS, Mohapatra DP, Misonou H, and Trimmer JS; Science, 2006 Aug 18;313(5789):976-9), which I looked up on PubMed. Words emphasized bring to bear the dynamic, graded nature of this study:

Dynamic modulation of ion channels by phosphorylation underlies neuronal plasticity. The Kv2.1 potassium channel is highly phosphorylated in resting mammalian neurons. Activity-dependent Kv2.1 dephosphorylation by calcineurin induces graded hyperpolarizing shifts in voltage-dependent activation, causing suppression of neuronal excitability. Mass spectrometry-SILAC (stable isotope labeling with amino acids in cell culture) identified 16 Kv2.1 phosphorylation sites, of which 7 were dephosphorylated by calcineurin. Mutation of individual calcineurin-regulated sites to alanine produced incremental shifts mimicking dephosphorylation, whereas mutation to aspartate yielded equivalent resistance to calcineurin. Mutations at multiple sites were additive, showing that variable phosphorylation of Kv2.1 at a large number of sites allows graded activity-dependent regulation of channel gating and neuronal firing properties.

We have billions of neurons. Various readings suggest 100-200 billion!