In excitation-contraction coupling of skeletal muscle, the dihydropyridine receptor (DHPR) of the T-tubule and the ryanodine receptor (RyR1) of the SR terminal cisternae are functionally coupled. In skeletal muscle (unlike cardiac muscle), how does DHPR activation cause RyR1 opening?

• A Ca2+-induced Ca2+ release: small Ca2+ influx through DHPR acting as an L-type calcium channel triggers RyR1 opening
• B IP3-mediated: DHPR activates phospholipase C, generating IP3 that opens RyR1 directly
• C Direct mechanical (conformational) coupling: DHPR acts as a voltage sensor transmitting a physical conformational change to RyR1 via protein-protein contact, opening it without Ca2+ influx ✓
• D cAMP-mediated: DHPR activates adenylyl cyclase, cAMP-PKA phosphorylates RyR1, opening it

Explanation

In skeletal muscle, the DHPR (which functions as a voltage sensor more than a Ca2+ channel) and RyR1 are physically linked by a mechanical coupling protein interaction at triadic junctions. Membrane depolarization causes a conformational change in DHPR, which is physically transmitted to RyR1 through their protein-protein contact (via the II-III loop of DHPR and the adjacent domain of RyR1), directly opening RyR1 and triggering Ca2+ release from the SR. This is fundamentally different from cardiac muscle, where CICR (Ca2+-induced Ca2+ release through RyR2) predominates because cardiac DHPR and RyR2 are not in direct mechanical contact.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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