Abstract
Sensory and behavioral plasticity are essential for animals to thrive in changing environments. As key effectors of intracellular calcium signaling, Ca2+/calmodulin-dependent protein kinases (CaMKs) can bridge neural activation with the many regulatory processes needed to orchestrate sensory adaptation, including by relaying signals to the nucleus. Here, we elucidate the molecular mechanism controlling the cell activation-dependent nuclear translocation of CMK-1, the Caenorhabditis elegans ortholog of mammalian CaMKI/IV, in thermosensory neurons in vivo. We show that an intracellular Ca2+ concentration elevation is necessary and sufficient to favor CMK-1 nuclear import. The binding of Ca2+/CaM to CMK-1 increases its affinity for IMA-3 importin, causing a redistribution with a relatively slow kinetics, matching the timescale of sensory adaptation. Furthermore, we show that this mechanism enables the encoding of opposite nuclear signals in neuron types with opposite calcium-responses and that it is essential for experience-dependent behavioral plasticity and gene transcription control in vivo. Since CaMKI/IV are conserved regulators of adaptable behaviors, similar mechanisms could exist in other organisms and for other sensory modalities.
Highlights
Behavioral adaptation is essential for animal survival in a continuously changing natural environment
CMK-1 cytoplasmic accumulation in unstimulated FLP neurons depends on an active transport and an intrinsic Nuclear Export Sequence Since CMK-1 subcellular localization varies according to cell-types and conditions, and since putative Nuclear Localization Sequences (NLS) and Nuclear Export Sequence (NES) are predicted from its primary sequence 37, CMK-1 localization may result from a dynamic equilibrium between nuclear import and export drives via canonical Export/Import pathways 38
Contrary to the predication made according to the NES masking model, we found that the triple mutant protein expression was cytoplasmic at 28°C, indistinguishable from that of the single W305S mutant (Fig. 3B). a functional NES288-294 element is dispensable for the cytosolic retention at 28°C of CaM binding-disruption mutant CMK-1
Summary
Behavioral adaptation is essential for animal survival in a continuously changing natural environment. AFD can detect tiny changes in temperature 17 and produce intracellular calcium transients in response to temperature elevations above a certain threshold, which depends on past thermosensory experience and which is determined by cell-autonomous mechanisms 18. Upon prolonged or repeated exposure to noxious heat, worms increase their thermal threshold for heat responsiveness through a desensitization, analgesia-like effect [3, 20] In both AFD and FLP, as well as additional sensory neurons, experience-dependent plasticity involves the cell-autonomous activity of the Calcium/Calmodulin (CaM)-dependent protein kinase-1 (CMK-1) 3, 21, 22, 23, 24. We show how long-term cell-autonomous calcium activity is integrated to regulate CMK-1 localization in FLP and AFD thermosensory neurons, and demonstrate the functional importance of this translocation mechanism in vivo. High intracellular calcium and Ca2+/CaM binding to CMK-1 unmask an NLS localized in the N-
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