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Summary Alternative splicing of pre-mRNAs is prominent in the mammalian brain, where it is thought to expand proteome diversity. For example, alternative splicing of voltage-gated Ca 2+ channel (VGCC) α 1 subunits can generate thousands of isoforms with differential properties and expression patterns. However, the impact of this molecular diversity on brain function, particularly on synaptic transmission, which crucially depends on VGCCs, is unclear. Here, we investigate how two major splice isoforms of P/Q-type VGCCs (Ca v 2.1[EFa/b]) regulate presynaptic plasticity in hippocampal neurons. We find that the efficacy of P/Q-type VGCC isoforms in supporting synaptic transmission is markedly different, with Ca v 2.1[EFa] promoting synaptic depression and Ca v 2.1[EFb] synaptic facilitation. Following a reduction in network activity, hippocampal neurons upregulate selectively Ca v 2.1[EFa], the isoform exhibiting the higher synaptic efficacy, thus effectively supporting presynaptic homeostatic plasticity. Therefore, the balance between VGCC splice variants at the synapse is a key factor in controlling neurotransmitter release and presynaptic plasticity. [ABSTRACT FROM AUTHOR]

Summary: CaV1.3 ion channels are dominant Ca2+ portals into pacemaking neurons, residing at the epicenter of brain rhythmicity and neurodegeneration. Negative Ca2+ feedback regulation of CaV1.3 channels (CDI) is therefore critical for Ca2+ homeostasis. Intriguingly, nearly half the CaV1.3 transcripts in the brain are RNA edited to reduce CDI and influence oscillatory activity. It is then mechanistically remarkable that this editing occurs precisely within an IQ domain, whose interaction with Ca2+-bound calmodulin (Ca2+/CaM) is believed to induce CDI. Here, we sought the mechanism underlying the altered CDI of edited channels. Unexpectedly, editing failed to attenuate Ca2+/CaM binding. Instead, editing weakened the prebinding of Ca2+-free CaM (apoCaM) to channels, which proves essential for CDI. Thus, editing might render CDI continuously tunable by fluctuations in ambient CaM, a prominent effect we substantiate in substantia nigral neurons. This adjustability of Ca2+ regulation by CaM now looms as a key element of CNS Ca2+ homeostasis. [Copyright &y& Elsevier]