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Deficiency of triad junction and contraction in mutant skeletal muscle lacking junctophilin type 1.

Ito K, Komazaki S, Sasamoto K, Yoshida M, Nishi M, Kitamura K, Takeshima H - J. Cell Biol. (2001)

Bottom Line: Of the three JP subtypes, both type 1 (JP-1) and type 2 (JP-2) are abundantly expressed in skeletal muscle.The mutant muscle developed less contractile force (evoked by low-frequency electrical stimuli) and showed abnormal sensitivities to extracellular Ca2+.Our results indicate that JP-1 contributes to the construction of triad junctions and that it is essential for the efficiency of signal conversion during E-C coupling in skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: Institute of Life Science, Kurume University and CREST, Japan Science and Technology Corporation, Fukuoka 839-0861, Japan.

ABSTRACT
In skeletal muscle excitation-contraction (E-C) coupling, the depolarization signal is converted from the intracellular Ca2+ store into Ca2+ release by functional coupling between the cell surface voltage sensor and the Ca2+ release channel on the sarcoplasmic reticulum (SR). The signal conversion occurs in the junctional membrane complex known as the triad junction, where the invaginated plasma membrane called the transverse-tubule (T-tubule) is pinched from both sides by SR membranes. Previous studies have suggested that junctophilins (JPs) contribute to the formation of the junctional membrane complexes by spanning the intracellular store membrane and interacting with the plasma membrane (PM) in excitable cells. Of the three JP subtypes, both type 1 (JP-1) and type 2 (JP-2) are abundantly expressed in skeletal muscle. To examine the physiological role of JP-1 in skeletal muscle, we generated mutant mice lacking JP-1. The JP-1 knockout mice showed no milk suckling and died shortly after birth. Ultrastructural analysis demonstrated that triad junctions were reduced in number, and that the SR was often structurally abnormal in the skeletal muscles of the mutant mice. The mutant muscle developed less contractile force (evoked by low-frequency electrical stimuli) and showed abnormal sensitivities to extracellular Ca2+. Our results indicate that JP-1 contributes to the construction of triad junctions and that it is essential for the efficiency of signal conversion during E-C coupling in skeletal muscle.

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Protein components involved in formation of triad junction in skeletal muscle. JP subtypes specifically interact with the cell membrane through the cytoplasmic region and span the ER–SR membrane in the COOH-terminal end. Therefore, JP subtypes can contribute to the formation of junctional membrane complexes. JP-1 knockout mice and other observations likely suggest that JP-1 is essential for the construction and/or maintenance of the triad junction in skeletal muscle (see text). In the triad junction, DHPR and RyR function as the cell surface voltage sensor and SR Ca2+ release channel, respectively, and proposed direct coupling between them converts depolarization into intracellular Ca2+ signaling. Furthermore, our previous results indicated that mitsugumin29 (MG29) is important for structural refinement of the triad junction, such as T-tubular vending and correct localization of the T-tubule (Nishi et al., 1999).
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fig8: Protein components involved in formation of triad junction in skeletal muscle. JP subtypes specifically interact with the cell membrane through the cytoplasmic region and span the ER–SR membrane in the COOH-terminal end. Therefore, JP subtypes can contribute to the formation of junctional membrane complexes. JP-1 knockout mice and other observations likely suggest that JP-1 is essential for the construction and/or maintenance of the triad junction in skeletal muscle (see text). In the triad junction, DHPR and RyR function as the cell surface voltage sensor and SR Ca2+ release channel, respectively, and proposed direct coupling between them converts depolarization into intracellular Ca2+ signaling. Furthermore, our previous results indicated that mitsugumin29 (MG29) is important for structural refinement of the triad junction, such as T-tubular vending and correct localization of the T-tubule (Nishi et al., 1999).

Mentions: JP subtypes are composed of a COOH-terminal hydrophobic segment spanning the ER–SR membrane and the remaining cytoplasmic region interacting with the PM. Based on the biochemical properties, JP can produce junctional membrane structures between the ER and the PM in a heterologous expression system. The heart predominantly contains JP-2, and the deficiency of peripheral coupling was observed in embryonic cardiac myocytes from the JP-2 knockout mice (Takeshima et al., 2000). Despite the fact that both JP-1 and JP-2 were expressed in skeletal muscle (Fig. 1) and that JP-1 deficiency did not affect the subcellular localization of JP-2 (Fig. 2), the JP-1 knockout muscle exhibited both ultrastructural and functional abnormalities. The reduction in total JP protein level might cause the abnormalities, although JP-1 and JP-2 are functionally similar. Alternatively, JP-1 and JP-2 might be functionally different, and JP-1 is essential for the formation and/or maintenance of triad junctions. The latter theory is likely supported by several observations: (1) the formation of triad junctions was specifically reduced in muscles other than the jaw muscle from the JP-1 knockout mice; (2) the expression of JP-1 and the formation of triad junctions significantly increase during muscle maturation after birth; and (3) only a few triad-like structures are detected in cardiac myocytes predominantly expressing JP-2. However, future studies will be needed to examine whether JP-1 and JP-2 are functionally and qualitatively different during the formation of skeletal muscle triad junctions. Although the molecular basis of the triad formation is largely unknown, recent gene knockout experiments pointed out protein components involved in the construction (Fig. 8) .


Deficiency of triad junction and contraction in mutant skeletal muscle lacking junctophilin type 1.

Ito K, Komazaki S, Sasamoto K, Yoshida M, Nishi M, Kitamura K, Takeshima H - J. Cell Biol. (2001)

Protein components involved in formation of triad junction in skeletal muscle. JP subtypes specifically interact with the cell membrane through the cytoplasmic region and span the ER–SR membrane in the COOH-terminal end. Therefore, JP subtypes can contribute to the formation of junctional membrane complexes. JP-1 knockout mice and other observations likely suggest that JP-1 is essential for the construction and/or maintenance of the triad junction in skeletal muscle (see text). In the triad junction, DHPR and RyR function as the cell surface voltage sensor and SR Ca2+ release channel, respectively, and proposed direct coupling between them converts depolarization into intracellular Ca2+ signaling. Furthermore, our previous results indicated that mitsugumin29 (MG29) is important for structural refinement of the triad junction, such as T-tubular vending and correct localization of the T-tubule (Nishi et al., 1999).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196186&req=5

fig8: Protein components involved in formation of triad junction in skeletal muscle. JP subtypes specifically interact with the cell membrane through the cytoplasmic region and span the ER–SR membrane in the COOH-terminal end. Therefore, JP subtypes can contribute to the formation of junctional membrane complexes. JP-1 knockout mice and other observations likely suggest that JP-1 is essential for the construction and/or maintenance of the triad junction in skeletal muscle (see text). In the triad junction, DHPR and RyR function as the cell surface voltage sensor and SR Ca2+ release channel, respectively, and proposed direct coupling between them converts depolarization into intracellular Ca2+ signaling. Furthermore, our previous results indicated that mitsugumin29 (MG29) is important for structural refinement of the triad junction, such as T-tubular vending and correct localization of the T-tubule (Nishi et al., 1999).
Mentions: JP subtypes are composed of a COOH-terminal hydrophobic segment spanning the ER–SR membrane and the remaining cytoplasmic region interacting with the PM. Based on the biochemical properties, JP can produce junctional membrane structures between the ER and the PM in a heterologous expression system. The heart predominantly contains JP-2, and the deficiency of peripheral coupling was observed in embryonic cardiac myocytes from the JP-2 knockout mice (Takeshima et al., 2000). Despite the fact that both JP-1 and JP-2 were expressed in skeletal muscle (Fig. 1) and that JP-1 deficiency did not affect the subcellular localization of JP-2 (Fig. 2), the JP-1 knockout muscle exhibited both ultrastructural and functional abnormalities. The reduction in total JP protein level might cause the abnormalities, although JP-1 and JP-2 are functionally similar. Alternatively, JP-1 and JP-2 might be functionally different, and JP-1 is essential for the formation and/or maintenance of triad junctions. The latter theory is likely supported by several observations: (1) the formation of triad junctions was specifically reduced in muscles other than the jaw muscle from the JP-1 knockout mice; (2) the expression of JP-1 and the formation of triad junctions significantly increase during muscle maturation after birth; and (3) only a few triad-like structures are detected in cardiac myocytes predominantly expressing JP-2. However, future studies will be needed to examine whether JP-1 and JP-2 are functionally and qualitatively different during the formation of skeletal muscle triad junctions. Although the molecular basis of the triad formation is largely unknown, recent gene knockout experiments pointed out protein components involved in the construction (Fig. 8) .

Bottom Line: Of the three JP subtypes, both type 1 (JP-1) and type 2 (JP-2) are abundantly expressed in skeletal muscle.The mutant muscle developed less contractile force (evoked by low-frequency electrical stimuli) and showed abnormal sensitivities to extracellular Ca2+.Our results indicate that JP-1 contributes to the construction of triad junctions and that it is essential for the efficiency of signal conversion during E-C coupling in skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: Institute of Life Science, Kurume University and CREST, Japan Science and Technology Corporation, Fukuoka 839-0861, Japan.

ABSTRACT
In skeletal muscle excitation-contraction (E-C) coupling, the depolarization signal is converted from the intracellular Ca2+ store into Ca2+ release by functional coupling between the cell surface voltage sensor and the Ca2+ release channel on the sarcoplasmic reticulum (SR). The signal conversion occurs in the junctional membrane complex known as the triad junction, where the invaginated plasma membrane called the transverse-tubule (T-tubule) is pinched from both sides by SR membranes. Previous studies have suggested that junctophilins (JPs) contribute to the formation of the junctional membrane complexes by spanning the intracellular store membrane and interacting with the plasma membrane (PM) in excitable cells. Of the three JP subtypes, both type 1 (JP-1) and type 2 (JP-2) are abundantly expressed in skeletal muscle. To examine the physiological role of JP-1 in skeletal muscle, we generated mutant mice lacking JP-1. The JP-1 knockout mice showed no milk suckling and died shortly after birth. Ultrastructural analysis demonstrated that triad junctions were reduced in number, and that the SR was often structurally abnormal in the skeletal muscles of the mutant mice. The mutant muscle developed less contractile force (evoked by low-frequency electrical stimuli) and showed abnormal sensitivities to extracellular Ca2+. Our results indicate that JP-1 contributes to the construction of triad junctions and that it is essential for the efficiency of signal conversion during E-C coupling in skeletal muscle.

Show MeSH
Related in: MedlinePlus