A Membrane Transistor

Voltage sensitive domains can make switches out of ion channels, antiporters, and other enzymes.

The heart of modern electronics is the transistor. It is a valve or switch, using a small electrical signal to control the flow of other electrical signals. We have learned that the simple logic this mechanism enables can be elaborated into hugely complex, even putatively intelligent, computers, databases, applications, and other paraphernalia of modernity. The same mechanism has a very long history in biology, quite apart from its use in neurons and brains, since membranes are typically charged, well-poised to be sensitive to changes in charge for all sorts of signaling.

The voltage sensitive domain (VSD) in proteins is an ancient (going back to archaea) bundle of four alpha helices that were first found attached to voltage-sensitive ion channels, including sodium, potassium, and calcium channels. But later it became fascinatingly apparent that it can control other protein activities as well. A recent paper discussed the mechanism and structure of a sodium/hydrogen antiporter with a role in sperm navigation, which uses a VSD to control its signaling. But there are also voltage-sensitive phosphatases, and other kinds of effectors hooked up to VSD domains. 

Schematic of a basic VSD, with helix 4 in pink, moving against the other three helices colored teal. Imagine a membrane going horizontally over these embedded proteins. When voltage across the local membrane changes, (hyperpolarized or de-polarized), helix 4 can plunge by one helical repeat unit in either direction, up or down.

One of the helixes (#4) in the VSD bundle has positive charges, while the others have specifically positioned negative charges. This creates a structure where changes in the ambient voltage across the membrane it sits in can cause helix #4 to plunge down by one or two steps (that is, turns of the alpha helix) versus its partners. This movement can then be propagated out along extensions of helix #4 to other domains of the protein in order to switch on or off their activities.

The helices of numerous proteins that have a VSD domain (in red) are drawn out, showing the diversity of how this domain is used.

While the studied protein, SLC9C1, is essential in mammalian sperm for motility, the paper studied its workings in sea urchin sperm, a common model system. The logic (as illustrated below) is that (female) chemoattractants bind to receptors on the sperm surface. These receptors generate cyclic GMP, which turns on potassium channels that increase the voltage across the membrane. This broadcasts the signal locally, and is received by the SLC9C1 transporter, which does two things. It activates a linked soluble adenylate cyclase enzyme, making the further signaling molecule cAMP. And it also activates the transporter itself, pumping protons out (in return 1:1 for sodium ions in) and causing cytoplasmic alkalinization. The cAMP activates sodium ion channels to cancel the high membrane voltage (a fast process), and the alkalinization activates calcium channels that direct the sperm directional swimming responses- the ultimate response. The latter is relatively slow, so the whole cascade has timing characteristics that allow the signal to be dampened, but the response to persist a bit longer as the sperm moves through a variable and stochastic gradient.

A schematic of the logic of this pathway, and of the SLC9C1 anti-porter. At top, the transport mechanism is crudely illustrated as a rocking motion that ensures that only one H+ is exchanged for one Na+ for each cycle of transport. The transport is driven thermodynamically by the higher concentration of Na+ outside.

But these researchers weren't interested in what the sperm were thinking, but rather how this widely used protein domain became hitched to this unusual protein and how it works there, turning on a sodium/hydrogen antiporter rather than the usual ion channel. They estimate that the #4 helix of the VSD moves by 10 angstroms, or 1 nm, upon voltage activation, which is a substantial movement, roughly equivalent to the width of these helices. In their final model, this movement significantly reshapes the intracellular domain of the transporter, which in turn releases its hold on the transporter's throat, allowing it to move cyclically as it needs to exchange hydrogen ions for sodium ions. This protein is known to bind and activate an adenylyl cyclase, which produces cAMP, which is one key next actor in the signaling cascade. This activation may be physically direct, or it may be through the local change in pH- that part is as yet unknown. cAMP also, incidentally, binds to and turns up the activity of this transporter, providing a bit of positive feedback.

Model of the SLC9C1 protein, with the VSD in teal and a predicted activation mechanism illustrated (only the third panel is activated/open). Upon voltage activation, the very long helix 4 dips down and changes orientation, dramatically opening the intracellular portion of the transporter (purple and orange portion). This in turn lets go of the bottom of the actual transporter portion of the protein (gray), allowing alkalinization of the cytoplasm to go forth. At the bottom sides, in brown, is the cAMP binding domain, which lowers the voltage threshold for activation.

There are a variety of interesting lessons from this work. One is that useful protein domains like VSD are often duplicated and propagated to unexpected places to regulate new processes. Another is that the new cryo-electron microscopy methods have made structural biology like this far easier and more common than it used to be, especially for membrane proteins, which are exceedingly difficult to crystalize. A third is that signaling systems in biology are shockingly complex. One would think that getting sperm cells to where they are going would take a bare minimum of complexity, yet we are studying a five or more part cascade involving two cyclic nucleotides, four ions, intricate proteins to manage them all, and who knows what else into the mix. It is difficult to account for all this, other than to say that when you have a few billion years to tinker with things, and have eons of desperate races to the egg for selective pressure, they tend to get more ornate. And a fourth is that it is regulatory switches all the way down.

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