Pivotal Role of the Lipid Raft SK3-Orai1 Complex in Human Cancer Cell Migration and Bone Metastases.

International audience: The SK3 channel, a potassium channel, was recently shown to control cancer cell migration, a critical step in metastasis outgrowth. Here, we report that expression of the SK3 channel was markedly associated with bone metastasis. The SK3 channel was shown to control constitutive Ca(2+) entry and cancer cell migration through an interaction with the Ca(2+) channel Orai1. We found that the SK3 channel triggers an association with the Orai1 channel within lipid rafts. This localization of an SK3-Orai1 complex seemed essential to control cancer cell migration. This suggests that the formation of this complex in lipid rafts is a gain-of-function, because we showed that none of the individual proteins were able to promote the complete phenotype. We identified the alkyl-lipid Ohmline as a disrupting agent for SK3-Orai1 lipid raft localization. Upon Ohmline treatment, the SK3-Orai1 complex moved away from lipid rafts, and SK3-dependent Ca(2+) entry, migration, and bone metastases were subsequently impaired. The colocalization of SK3 and Orai1 in primary human tumors and bone metastases further emphasized the clinical relevance of our observations. Targeting SK3-Orai1 in lipid rafts may inaugurate innovative approaches to inhibit bone metastases. Cancer Res; 73(15); 1-10. ©2013 AACR

Integration and propagation of somatosensory responses in the corticostriatal pathway: an intracellular study in vivo

The dorsolateral striatum is critically involved in the execution and learning of sensorimotor tasks. It is proposed that this striatal function is achieved by the integration of convergent somatosensory and motor corticostriatal (CS) inputs in striatal medium-spiny neurons (MSNs). However, the cellular mechanisms of integration and propagation of somatosensory information in the CS pathway remain unknown. Here, by means of in vivo intracellular recordings in the rat, we analysed how sensory events generated by multi-whisker deflection, which provide essential somaesthetic information in rodents, are processed in contralateral barrel cortex layer 5 neurons and in the related somatosensory striatal MSNs. Pyramidal layer 5 barrel cortex neurons, including neurons antidromically identified as CS, responded to whisker deflection by depolarizing postsynaptic potentials that could reliably generate action potential discharge. In contrast, only half of recorded somatosensory striatal MSNs displayed whisker-evoked synaptic depolarizations that were effective in eliciting action potentials in one-third of responding neurons. The remaining population of MSNs did not exhibit any detectable electrical events in response to whisker stimulation. The relative inconstancy of sensory-evoked responses in MSNs was due, at least in part, to a Cl−-dependent membrane conductance concomitant with the cortical inputs, which was probably caused by whisker-induced activation of striatal GABAergic interneurons. Our results suggest that the propagation of whisker-mediated sensory flow through the CS pathway results in a refinement of sensory information in the striatum, which might allow the selection of specific sets of MSNs that are functionally significant during a given somaesthetic-guided behaviour