Tau isoform-specific enhancement of L-type calcium current and augmentation of afterhyperpolarization in rat...

Accumulation of tau is observed in dementia, with human tau displaying 6 isoforms grouped by whether they display either 3 or 4 C-terminal repeat domains (3R or 4R) and exhibit no (0N), one (1N) or two (2N) N terminal repeats. Overexpression of 4R0N-tau in rat hippocampal slices enhanced the L-type calcium (Ca²⁺) current-dependent components of the medium and slow afterhyperpolarizations (AHPs). Overexpression of both 4R0N-tau and 4R2N-tau augmented Ca_V1.2-mediated L-type currents when expressed in tsA-201 cells, an effect not observed with the third 4R isoform, 4R1N-tau. Current enhancement was only observed when the pore-forming subunit was co-expressed with Ca_Vβ3 and not Ca_Vβ2a subunits. Non-stationary noise analysis indicated that enhanced Ca²⁺ channel current arose from a larger number of functional channels. 4R0N-tau and Ca_Vβ3 were found to be physically associated by co-immunoprecipitation. In contrast, the 4R1N-tau isoform that did not augment expressed macroscopic L-type Ca²⁺ current exhibited greatly reduced binding to Ca_Vβ3. These data suggest that physical association between tau and the Ca_Vβ3 subunit stabilises functional L-type channels in the membrane, increasing channel number and Ca²⁺ influx. Enhancing the Ca²⁺-dependent component of AHPs would produce cognitive impairment that underlie those seen in the early phases of tauopathies.