Getting the N type calcium channels in the crosshairs

Yale has enjoyed an unusual reputation for pain research, but recent progress at its neighbor, Brown University, home of one of the authors at painonline, shows the people at Brown are awesome also.

Although we have not received any correspondence begging us to stop talking about the synapse and ion channels, we suspect some of you are finding it tiresome to have to buckle down and learn this stuff. However, it is your salvation so take notice of what is going on.

Castiglioni et al have been eyeing the evil little Calcium channels of the type which cause pain; namely the N-type channels. However, there is more than one type and the subtypes have subtypes, so it is necessary to pinpoint the real evildoer and Castiglioni may have done it. See J Physiol. 2006 Oct 1;576(Pt 1):119-34.

You are aware that pain neurons are known as nociceptors. Where they terminate at a synapse, nociceptors have a unique set of ion channels and receptors which control release of pain neurotransmitters.

N-type Ca(V)2.2 calcium channels (see prior articles on these using SEARCH at this site) are found in PRE-synaptic nerve terminals. Different types of the 2.2 channel are called “isoforms”. Castiglioni et al have identified the isoform Ca(V)2.2e[37a] as being THE pain isoform. Other 2.2 channels have the 37b C terminus. Bingo! Now we are getting somewhere. It would appear that 37b and 37a are mutally exclusive. A channel has to take its choice, it cannot have both types of terminal ending. Remember that such work is actually done by studying the messenger RNA which signifies the presence of the actual end product which is much more difficult to measure. So it is really 37a mRNA that we are talking about in this study.

These researchers studied both ionic and gating currents associated with 37a. Castiglioni states:

“When activated, Ca(V)2.2e[37a] channels remain open for longer and are expressed at higher density than Ca(V)2.2e[37b] channels. These unique features of the Ca(V)2.2e[37a] isoform combine to augment substantially the amount of calcium that enters cells in response to action potentials*. Our studies of the e37a/e37b splice site reveal a multifunctional domain in the C-terminus of Ca(V)2.2 that regulates the overall activity of N-type calcium channels in nociceptors.”

In other words, scientists think they may have the bad boy which allows calcium to flood the synapse, which pours out the glutamate, which spews out the NMDA, which makes you burn. Of course, the next step is to block 37a. Calcium channels are made up of subunits in various ratios, known by letters of the Greek alphabet (alpha, beta etc.). Each little component may be targeted. For example, Lyrica acts on the alpha2-delta-1 subunit; and knockout mice for the Ca(v)2.1 alpha1 subunit are less prone to certain other pain.

All we can say is thank you to the people who do this kind of work. It is not easy, but it is the drop of water on our Lazarus tongue of desire to see Central Pain end, so we can be brought back to life. Hopefully, we will soon drink to the fullest.

*An action potential simply means a nerve firing or nerve signal, a blip on the screen, as it were.