Calcium-induced calcium release — CICR — in a cardiac/muscle cell

One-line summary

A small Ca²⁺ influx through L-type Ca²⁺ channels (LTCC) on the T-tubule membrane triggers a much larger Ca²⁺ release from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyR); that cytosolic Ca²⁺ rise produces contraction and is then rapidly cleared so the cell can relax.

Step-by-step

  1. Resting state

    • Cytosolic free Ca²⁺ is very low (~100 nM).

    • The SR lumen stores Ca²⁺ at a much higher concentration (order of 0.5–1 mM, bound to buffering proteins such as calsequestrin).

    • The T-tubule system sits close to junctional SR to form dyads (small signalling microdomains).

  2. Electrical trigger (depolarisation — phase 0)

    • An action potential travels along the sarcolemma and into the T-tubules, depolarising the membrane locally.

  3. Opening of L-type Ca²⁺ channels (LTCC / DHPR)

    • Depolarisation opens voltage-gated LTCCs in the T-tubule membrane.

    • A small, local inward Ca²⁺ current flows from the extracellular space into the narrow dyadic cleft. This is called the trigger Ca²⁺.

  4. Activation of ryanodine receptors (RyR2) on the SR

    • The small trigger Ca²⁺ rapidly reaches the RyR channels on the junctional SR.

    • RyR2 are Ca²⁺-sensitive: binding of trigger Ca²⁺ increases their open probability.

  5. Massive SR Ca²⁺ release — CICR

    • Once RyR2 open, a large volume of Ca²⁺ floods from the SR lumen into the cytosol (many local “Ca²⁺ sparks” sum to produce the global Ca²⁺ transient).

    • This amplification is the essence of calcium-induced calcium release (CICR).

  6. Contraction

    • Cytosolic Ca²⁺ concentration rises (typically to ~0.5–1 μM).

    • Ca²⁺ binds troponin C, causing tropomyosin to move and allowing actin–myosin cross-bridge cycling → muscle contraction.

  7. Termination of release and relaxation

    • RyR channels close (release diminishes).

    • Cytosolic Ca²⁺ is lowered by:

      • SERCA (SR Ca²⁺-ATPase) pumping Ca²⁺ back into the SR (major route).

      • Na⁺/Ca²⁺ exchanger (NCX) on the sarcolemma extruding Ca²⁺ in exchange for Na⁺.

      • Plasma membrane Ca²⁺-ATPase (PMCA) contributes a minor amount.

    • As cytosolic Ca²⁺ falls, troponin releases Ca²⁺ and the muscle relaxes.

  8. Refilling the SR

    • SERCA activity refills SR stores; SR proteins (calsequestrin) help buffer high luminal Ca²⁺.

    • The cell is then ready for the next action potential.

Key components and terms

  • LTCC (L-type Ca²⁺ channel / dihydropyridine receptor) — located in T-tubules; provides trigger Ca²⁺.

  • RyR (ryanodine receptor, mainly RyR2 in heart) — SR release channel; mediates CICR.

  • Sarcoplasmic reticulum (SR) — intracellular Ca²⁺ store.

  • Dyad / junctional SR — very small cleft where LTCC and RyR face each other for fast signalling.

  • SERCA — SR Ca²⁺-ATPase that pumps Ca²⁺ back into SR (regulated by phospholamban).

  • NCX (Na⁺/Ca²⁺ exchanger) — extrudes Ca²⁺ across the cell membrane.

Modulation & physiological relevance

  • β-adrenergic stimulation (fight/flight) → PKA phosphorylation increases LTCC open probability and relieves phospholamban inhibition of SERCA → larger, faster Ca²⁺ transients and stronger, quicker contractions.

  • Dysregulation (excessive RyR leak or impaired SERCA) contributes to arrhythmias and heart failure because Ca²⁺ handling is central to both contraction and electrical stability.

  • Drugs that affect LTCC (calcium-channel blockers) alter the trigger current and thus contractility and rhythm.

Quick numeric flavour

  • Resting cytosolic Ca²⁺ ≈ 100 nM → peak during systole ≈ 0.5–1 μM (rough figures).

  • SR luminal Ca²⁺ ≈ ~0.5–1 mM (buffered).

Short final summary

CICR is a local amplification mechanism: a small extracellular Ca²⁺ entry (via LTCC) triggers large SR Ca²⁺ release (via RyR), producing the cytosolic Ca²⁺ transient that drives contraction — after which pumps and exchangers restore basal Ca²⁺ levels so the cell can relax and repeat the cycle.