Calcium ions (Ca2+) that enter a cell through L-type voltage-activated channels (LTCs) are linked to expression of certain genes involved in key neuronal functions, whereas Ca2+ entering the cell by other means can exert different effects. Dolmetsch et al. (Perspective by Ikeda) use a clever strategy to explore this perplexing aspect of specificity in cell signaling. They first engineered an LTC that is resistant to a channel inhibitor and then expressed and analyzed it in cultured primary neurons that were treated with the inhibitor to eliminate endogenous channel function. A calmodulin-binding region of the LTC is essential for Ca2+-induced activation of the transcription factors CREB and MEF-2. Thus, the Ca2+ entering though LTCs is apparently sensed by calmodulin molecules already positioned at the mouth of the channel. This activation of calmodulin is required for sustained activation of the p42 and p44 mitogen-activated protein kinases, which in turn convey the signal on into the nucleus.
R. E. Dolmetsch, U. Pajvani, K. Fife, J. M. Spotts, M. E. Greenberg, Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 294, 333-339 (2001). [Abstract] [Full Text]