Polycystin 2 (PC2) is a calcium-dependent calcium channel, and mutations to human PC2 (hPC2) are associated with polycystic kidney disease. The C-terminal tail of hPC2 contains 2 EF hand motifs, but only the second binds calcium. Here, we investigate whether these EF hand motifs serve as a calcium sensor responsible for the calcium dependence of PC2 function. Using NMR and bioinformatics, we show that the overall fold is highly conserved, but in evolutionarily earlier species, both EF hands bind calcium. To test whether the EF hand motif is truly a calcium sensor controlling PC2 channel function, we altered the number of calcium binding sites in hPC2. NMR studies confirmed that modified hPC2 binds an additional calcium ion. Single-channel recordings demonstrated a leftward shift in the calcium dependence, and imaging studies in cells showed that calcium transients were enhanced compared with wild-type hPC2. However, biophysics and functional studies showed that the first EF hand can only bind calcium and be functionally active if the second (native) calcium-binding EF hand is intact. These results suggest that the number and location of calcium-binding sites in the EF hand senses the concentration of calcium required for PC2 channel activity and cellular function.

MicroRNAs control gene expression by inhibiting translation or promoting degradation of their target mRNAs. Since the discovery of the first microRNAs, lin-4 and let-7, in C. elegans, hundreds of microRNAs have been identified as key regulators of cell fate determination, lifespan, and cancer in species ranging from plants to humans. However, while microRNAs have been shown to be particularly abundant in the brain, their role in the development and activity of the nervous system is still largely unknown. In this review, we describe recent advances in our understanding of microRNA function at synapses, the specialized structures required for communication between neurons and their targets. We also propose how these advances might inform the molecular model of memory.

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