Intro to Pharmacology and Toxicology
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The influx of Ca2+ through plasma membrane channels is very small ( ~ 500 nM to 1 µM), so it has little effect on cells. It mostly generates Ca2+-induced Ca2+ release (CICR) from intracellular stores.
In smooth and cardiac muscle, L-type calcium channels are located in T-tubules of the sarcoplasm, very close to the sarcoplasmic reticulum (SR). When an action potential invades the T-tubules, L-type channels open and allow Ca2+ in, which in turn bind to ryodine receptors in the SR, signaling the release of Ca2+ from the SR stores. The rush of Ca2+ into the cytoplasm signals muscle cells to contract. To end the contraction, Ca2+ is taken up by the SR using SERCA (sarco/endoplasmic reticulum calcium ATPase) pumps, and calciquestrin in the SR binds 40 Ca2+ per mol. Also, Ca2+ from the SR deactivates L-type channels.
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If the rate of change of the Ca2+ concentration by L-type channel influx is not enough to trigger a response, the SR does not release Ca2+ but is recharged through the SERCA pumps. The two key features that produce a muscle contraction are the rate of Ca2+ increase and its localization. IP3 can lead to Ca2+ waves/oscillations over time. Although it is not clear why, this mechanism may be important for transcription. Depending on the cell type, IP3 leads to transient or sustain Ca2+ release.
The Berridge Two Pool Model tries to explain the mechanism of IP3 signaling of Ca2+ release and it works both through agonist gated channels (secretory cells) and voltage-gated channels (neurons). According to the model, one pool of Ca2+ is sensitive to IP3, the other is not. An unknown mechanism in the plasma or ER membrane senses that Ca2+ stores are low and signals channels to refill. An agonist triggers the cytoplasmic increase of IP3, which in turn activates plasma membrane Ca2+ channels. The initial influx is used to refill intracellular stores. When stores are full, IP3 signals the IP3 sensitive stores to release Ca2+. Some of the released Ca2+ in turn signals other internal Ca2+ stores (non-/IP3 sensitive) to release Ca2+. This accounts for the oscillations observed during IP3- triggered Ca2+ release, as different pools open for release in succession.
At the end there is a recovery phase where Ca2+ is pumped out of the cell or into internal stores. This complete pathway has very sharp dependence on IP3 concentrations.
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