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PNAS 103 (28): 10811-10816

Copyright © 2006 by the National Academy of Sciences.


Functional uncoupling between Ca2+ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins

Shigeki Moriguchi*,{dagger}, Miyuki Nishi{dagger},{ddagger},§, Shinji Komazaki, Hiroyuki Sakagami||, Taisuke Miyazaki**, Haruko Masumiya{ddagger}, Shin-ya Saito{ddagger}, Masahiko Watanabe**, Hisatake Kondo||, Hiromu Yawo{dagger}{dagger}, Kohji Fukunaga*, and Hiroshi Takeshima{ddagger},§,{ddagger}{ddagger}

*Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Departments of {ddagger}Medical Chemistry and ||Cell Biology, Graduate School of Medicine, and {dagger}{dagger}Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai 980, Japan; §Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606, Japan; Department of Anatomy, Saitama Medical School, Saitama 350, Japan; and **Department of Anatomy, Graduate School of Medicine, Hokkaido University, Sapporo 060, Japan

Edited by Clara Franzini-Armstrong, University of Pennsylvania School of Medicine, Philadelphia, PA, and approved May 31, 2006

Received for publication November 14, 2005.

Abstract: Junctional membrane complexes (JMCs) composed of the plasma membrane and endoplasmic/sarcoplasmic reticulum seem to be a structural platform for channel crosstalk. Junctophilins (JPs) contribute to JMC formation by spanning the sarcoplasmic reticulum membrane and binding with the plasma membrane in muscle cells. In this article, we report that mutant JP double-knockout (JP-DKO) mice lacking neural JP subtypes exhibited an irregular hindlimb reflex and impaired memory. Electrophysiological experiments indicated that the activation of small-conductance Ca2+-activated K+ channels responsible for afterhyperpolarization in hippocampal neurons requires endoplasmic reticulum Ca2+ release through ryanodine receptors, triggered by NMDA receptor-mediated Ca2+ influx. We propose that in JP-DKO neurons lacking afterhyperpolarization, the functional communications between NMDA receptors, ryanodine receptors, and small-conductance Ca2+-activated K+ channels are disconnected because of JMC disassembly. Moreover, JP-DKO neurons showed an impaired long-term potentiation and hyperactivation of Ca2+/calmodulin-dependent protein kinase II. Therefore, JPs seem to have an essential role in neural excitability fundamental to plasticity and integrated functions.

Key Words: hippocampus • learning and memory • long • term potentiation • ryanodine receptor • SK channel

{dagger}S.M. and M.N. contributed equally to this work.

Author contributions: S.M., M.N., S.K., H.S., T.M., and H.T. designed research; S.M., M.N., S.K., H.S., T.M., H.M., M.W., H.Y., and H.T. performed research; S.-y.S., M.W., H.K., K.F., and H.T. analyzed data; and H.T. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

{ddagger}{ddagger}To whom correspondence should be addressed. E-mail: takeshim{at}

© 2006 by The National Academy of Sciences of the USA

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