The primary language of excitable cells (action potential firing) is converted into the primary language of intracellular activity (biochemical signaling) by voltage-gated Ca2+ channels (CaVs) – a key part of “excitation-response coupling”. This kind of signaling is vividly exemplified by excitation-contraction (E-C) coupling and excitation-secretion (E-S) coupling, processes respectively described by Hodgkin, Huxley and their colleagues, and by Katz and Miledi, Llinas, and Douglas, mostly in The Journal of Physiology. Over the intervening decades, much has been learned about molecular mechanisms of E-C and E-S coupling. Excitation-transcription (E-T) coupling, the topic of this lecture, is arguably a more general event in neurons and other excitable cells. However, in contrast to E-C and E-S coupling, E-T coupling is much less understood at a mechanistic level. It is generally accepted that one particular class of Ca2+ channels, CaV1 (also known as L-type channels) has a privileged role in excitation-transcription coupling to nuclear CREB, a transcription factor critical in learning and memory. However, the mechanism of even the earliest step in this signaling pathway is not well understood: local Ca2+ elevations in the nanodomain of CaV1 channels are thought to be the main trigger in the signaling cascade, but CaV1 channels could also convey a voltage-dependent conformational signal (VCS) to nearby signaling intermediates, analogous to the conformational signal in E-C coupling. We have devised an approach where conformational changes required to open the CaV pore are experimentally decoupled from Ca2+ influx into the channel nanodomain. This molecular dissection uncovered a remarkable and unexpected requirement for the CaV1 VCS in excitation-transcription coupling. CaV1 signaling to CREB behaves as a coincidence detector, where both Ca2+ and voltage-dependent movements are necessary. Another puzzle is how local signaling at CaV1 channels is relayed onward to the nucleus. We have discovered a novel mechanism that mediates long-distance communication within cells: a shuttle that transports Ca2+ /calmodulin from the surface membrane to the nucleus. We find that the shuttle protein is γCaMKII, that its phosphorylation at Thr287 by βCaMKII protects the Ca2+ /CaM signal, and that calcineurin (CaN) triggers its nuclear translocation. Both βCaMKII and CaN act in close proximity to CaV1 channels, supporting their dominance, while γCaMKII operates as a carrier, not as a kinase. Upon arrival within the nucleus, Ca2+ /CaM activates CaMKK and its substrate CaMKIV, the CREB kinase. This mechanism resolves longstanding puzzles about CaM/CaMK-dependent signaling to the nucleus. The significance of the mechanism is emphasized by dysregulation of CaV1, γCaMKII, βCaMKII and CaN in multiple neuropsychiatric disorders.