Functional uncoupling between Ca2+ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins.
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 Ca(2+)-activated K(+) channels responsible for afterhyperpolarization in hippocampal neurons requires endoplasmic reticulum Ca(2+) release through ryanodine receptors, triggered by NMDA receptor-mediated Ca(2+) influx. We propose that in JP-DKO neurons lacking afterhyperpolarization, the functional communications between NMDA receptors, ryanodine receptors, and small-conductance Ca(2+)-activated K(+) channels are disconnected because of JMC disassembly. Moreover, JP-DKO neurons showed an impaired long-term potentiation and hyperactivation of Ca(2+)/calmodulin-dependent protein kinase II. Therefore, JPs seem to have an essential role in neural excitability fundamental to plasticity and integrated functions.
Moriguchi
Shigeki
S
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Graduate School of Medicine, Tohoku University, Sendai 980, Japan.
Nishi
Miyuki
M
Komazaki
Shinji
S
Sakagami
Hiroyuki
H
Miyazaki
Taisuke
T
Masumiya
Haruko
H
Saito
Shin-Ya
SY
Watanabe
Masahiko
M
Kondo
Hisatake
H
Yawo
Hiromu
H
Fukunaga
Kohji
K
Takeshima
Hiroshi
H
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D008564:Membrane Potentials / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000502:physiology
C481843:Jph4 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C412507:junctophilin; D002118:Calcium