Multiple antagonist calcium-dependent mechanisms control CaM kinase-1 subcellular localization in a <i>C. elegans</i> thermal nociceptor.

Abstract

Nociceptive habituation is a conserved process through which pain sensitivity threshold is adjusted based on past sensory experience and which may be dysregulated in human chronic pain conditions. Noxious heat habituation in <i>Caenorhabditis elegans</i> involves the nuclear translocation of CaM kinase-1 (CMK-1) in the FLP thermo-nociceptors neurons, causing reduced animal heat sensitivity and avoidance responses. The phosphorylation of CMK-1 on T179 by CaM kinase kinase-1 (CKK-1) is required for nuclear entry. Recently, we identified a specific nuclear export sequence (NES) required to maintain CMK-1 in the cytoplasm at rest (20°C) and showed that Ca²⁺/CaM binding is sufficient to enhance CMK-1 affinity for IMA-3 via a specific nuclear localization signal (NLS) in order to promote nuclear entry after persistent heat stimulation (90 min at 28°C) (Ippolito et al., 2021). Here, we identified additional functional NES and NLS on CMK-1, whose activity can counteract previously identified elements. Furthermore, we clarify the relationship between the CaM-binding-dependent and T179-dependent effects. T179 phosphorylation can promote nuclear entry both downstream of CaM binding and as part of an independent/parallel pathway. Moreover, T179 phosphorylation can also produce the opposite effect by promoting nuclear export. Taken together, our studies suggest that multiple calcium-dependent regulatory mechanisms converge to bias the activity pattern across a network of NES/NLS elements, in order to control CMK-1 nucleo-cytoplasmic shuttling, and actuate stimulation-dependent nociceptive plasticity.