ABSTRACT In neuronal excitation-transcription (E-T) coupling, electrical signals at somatodendritic membranes drive transcriptional activation in the nucleus, tens or hundreds of micrometers away. E-T coupling is critical for long- term adaptation, synaptic plasticity, development and memory; it can go awry in brain disorders. Voltage-gated L-type Ca2+ channels (LTCCs) play a dominant role in E-T coupling. Switching on these Ca2+ channels initiates a cascade that causes activation of a nuclear transcription factor CREB (Ca2+- and cAMP- response element binding protein), heavily studied because of its importance for learning and memory. This proposal concerns signaling mechanisms that connect activation of LTCCs to CREB phosphorylation and other nuclear events. We recently found that excitatory neurons use two distinct signals to mediate E-T coupling: a local rise in Ca2+ and a voltage-dependent conformational change (VΔC) of the LTCC, akin to the VΔC that triggers contraction of skeletal muscle. Even with LTCC Ca2+ influx blocked, VΔC synergistically augmented CaMKII mobilization to dendritic spines initiated by NMDA receptor stimulation and greatly enhanced the phospho-CREB response. Such cooperation between glutamatergic input (NMDAR) and electrical signaling (VΔC) operates like a temporal proximity detector, of likely significance for synaptic plasticity. We will address new questions about mechanistic components, impact on synaptic and molecular dynamics, and signaling from neuronal subregions. First, we will make designer L-type channels to determine how Ca2+ channelCaMKII communication comes about. Second, we will test a mechanstic model for the multiple steps between CaMKII liberation and mobilization to synaptic sites, its dwell at NMDARs and its eventual conformation-sensitive LTCC trapping. Third, we will delineate the potency of local subregions to control nuclear transcription and gauge the impact of synaptic L-type channelCaMKII signaling on immediate and 24 h changes in synaptic strength, of relevance to multiple brain disorders, including neuropsychiatric diseases and Alzheimer’s disease.