In muscle, junctophilins (JPs) contribute to the formation of the junctional membrane complexes (JMCs) that couple plasma membrane ion channels to ryanodine receptors (RyRs) in the sarcoplasmic reticulum. Two JP subtypes, JP-3 and JP-4, are found in neurons; here, their functions are less clear. Moriguchi et al. found that, although double knockout mice lacking JP-3 and JP-4 (JP-DKO mice) displayed apparently normal brain morphology, with JMCs apparent by electron microscopy in hippocampal neurons and normal forebrain expression of major endoplasmic reticulum (ER)-related proteins (determined by Western analysis), behavioral analyses showed impaired memory. The mice also showed an abnormal "foot-clasping reflex" when suspended by the tail. Whole-cell current clamp analysis revealed that action potentials recorded from CA1 pyramidal cells in hippocampal slices from JP-DKO mice lacked an after-hyperpolarization (AHP) mediated by small-conductance Ca2+-dependent K+ (SK) channels, although SK subtypes normally present in hippocampus were expressed. The AHP was abolished in wild-type mice by blockade of NMDARs, depletion of ER calcium stores with cyclopiazonic acid, or inhibition of RyR-mediated calcium release. These treatments had no apparent effect on JP-DKO neurons, although calcium-imaging analysis revealed normal calcium transients in response to caffeine. JP-DKO mice also showed impaired long-term potentiation (LTP) of CA1 synaptic plasticity, as well as enhanced basal phosphorylation of Ca2+/calmodulin-dependent protein kinase II. The authors propose that SK activation and development of the AHP in CA1 neurons involves a Ca2+-mediated functional coupling between NMDARs, RyRs, and SK channels that depends on JPs.
S. Moriguchi, M. Nishi, S. Komazaki, H. Sakagami, T. Miyazaki, H. Masumiya, S.-y. Saito, M. Watanabe, H. Kondo, H. Yawo, K. Fukunaga, H. Takeshima, Functional uncoupling between Ca2+ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins. Proc. Natl. Acad. Sci. U.S.A. 103, 10811-10816 (2006). [Abstract] [Full Text]
