A Ca 2+ Connection

Abstract

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 Ca 2+ -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 Ca 2+ /calmodulin-dependent protein kinase II. The authors propose that SK activation and development of the AHP in CA1 neurons involves a Ca 2+ -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 Ca 2+ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins. Proc. Natl. Acad. Sci. U.S.A. 103 , 10811-10816 (2006). [Abstract] [Full Text]