A key event in excitation contraction (e-c) coupling of skeletal and cardiac muscles is the rapid release
of Ca²⁺ from the internal membrane-limited system, the sarcoplasmic reticulum (SR), under the control
of the exterior membranes (surface membrane and transverse, T tubules). Functional interaction between
exterior and interior membrane systems involves two Ca²⁺ permeant channels: the dihydropyridine receptors
(DHPRs, or L type Ca²⁺ channels) of exterior membranes and the ryanodine receptors (RyRs) or Ca²⁺ release
channel of the SR. SR and exterior membranes interact with each other at intracellular junctions called
calcium release units. Understanding the topology and geometry of muscle membranes and the spatial
relationship between the key molecules within the calcium release units is essential to unraveling the mechanism
of regulated Ca²⁺ release during activation of muscle contraction. Important clues are provided by functional
and structural similarities as well as differences between skeletal and cardiac muscle. In both types of muscle
fibers, RyRs are visible as “feet”, located in orderly arrays within the junctional gap between SR and
exterior membranes. In skeletal muscle, DHPRs are grouped into groups of four (tetrads) and the tetrads
are clustered in arrays that precisely overlap the arrays of RyRs. In cardiac muscle, arrays of RyRs are associated
with clusters of DHPRs, but the DHPRs do not form an orderly arrangement. We proposed that the formation
of tetrads by DHPRs in skeletal muscle is indicative of a linkage between four DHPRs and the four subunits of
the RyR. Conversely, lack of tetrads in cardiac muscle indicate that such link is not present. This hypothesis is
directly confirmed by observations on a cell line (1B5) derived from a mouse with a null mutation of RyR1,
the skeletal isoform. In differentiated 1B5 cells, calcium release units are “dyspedic”: feet are absent from
the junctional gap. DHPRs are clustered at the junctions as in normal cells, but do not form tetrads. Transfection
with cDNA for RyR1 results in rescue of the junctional structure: feet are present and DHPRs form tetrads and
tetrad arrays.

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