Intracellular calcium - Transfers
Penetration into the cell.
The penetration of calcium into cells is carried out by different structures:
- The Na+/Ca2+ exchanger when it functions inversely to the usual direction, i.e. efflux of sodium and influx of calcium.
- The receptor-dependant calcium channels, sometimes called voltage-independent calcium channels, whose opening depends on activation of receptors by their agonists and by a factor called CIF (Cytoplasmic calcium impulse Factor), released when the intracytoplasmic calcium concentration falls.
- The channels dependant on membrane potential, called voltage-gated calcium channels which open during depolarization and induce calcium entry. The T type channel opens at a low potential, other types, L, N, P, Q and R types open at high potential. The L, T and N channels are the main targets of drugs. Their distribution differs according to tissues. The L channels are the best known.
- L-type channel (L for Long because it has long opening. This opening is induced by cell depolarization (-20 mv with -10 mv) and hypoxia. This channel is permeable to calcium, barium and strontium ions. For being able to open during depolarization, L channels, must be phosphorylated by proteins kinases which depend on CAMP and thus on the effect of certain transmitters such as norepinephrine. The rise of calcium inside the cytoplasm induces their closure. The L type channels are abundant in heart, skeletal muscles and vascular smooth muscles. The drug of reference, inhibiting opening of type L channels, is nifedipine. There are, on the other hand, compounds such as certain toxins, inducing their opening.
- T- type channel (T for transient) because their duration of opening is very short. It opens at a lower potential (from -90 to -30 mv) than the type L channel and is inactivated quickly with depolarization.
- N- type channel (N for neuron because present in neurons), is well-known. It is inhibited by a neurotoxic peptide, conotoxine, and by some antiepileptic drugs.
Efflux out of the cell
Calcium leaves the cell primarily through the calcium-ATPASE pump which uses the energy provided by the hydrolysis of the ATP. This pump is stimulated by the calcium-calmodulin complex and is inhibited by lanthanum and vanadate.
The Na+/Ca2+ exchanger under the usual conditions extrudes one Ca2+ ion and enters two or three Na+ ions.
Intracellular exchanges
The calcium concentration in the cytoplasm is extremely low because, in addition to the mechanisms of regulation of its exchanges with the extracellular medium, there are cell organelles likely to collect it. These organelles are the sarcoplasmic reticulum, the mitochondria and the cellular nucleus.
- Sarcoplasmic reticulum
The calcium uptake by the sarcoplasmic reticulum is carried out by the calcium-ATPase pump which is activated by phospholamban. In muscles, the acceleration of the reuptake of calcium shortens the duration of the contraction.
The calcium release from the sarcoplasmic reticulum in the cytoplasm, is carried out via at least two types of channels:
- IP3 receptors channels whose opening is stimulated by inositol triphosphate, IP3.
- ryanodine receptor channels. They are called thus because ryanodine, alkaloid of vegetable origin not used in therapeutics, binds them specifically and can, according to its concentrations, either inhibit them, or activate them. The increase in the concentration of intracytoplasmic calcium induces calcium release by the ryanodine receptor channel; magnesium has the inverse effect. Cyclic adenosine diphosphate ribose, cADPR, which results from the transformation of beta-NAD under the influence of the ADPR cyclase, is regarded as the endogenous activator of this receptor. The activity of the ADPR cyclase is stimulated by retinoic all-trans acid. The ryanodine receptors are present especially at the level of the cardiac and skeletal muscles.
Caffeine and halothane increase the release of calcium from the sarcoplasmic reticulum whereas magnesium and dantrolene inhibit it.
Malignant hyperthermias with muscular rigidity, sometimes observed after anesthesia with halothane, could be the consequence of the increase of calcium release by the sarcoplasmic reticulum because of an anomaly of ryanodine receptors. Dantrolene is used to treat these hyperthermias.
- Mitochondria
There are transfers of calcium between the cytoplasm and mitochondria: calcium penetrates into mitochondria via a specific carrier. It leaves mitochondria by a sodium exchanger. The inhibition of this exchanger induces an increase in intramitochondrial Ca2+.
- Cellular nucleus
There are also transfers of calcium between the cytoplasm and the nucleus by not well known mechanisms. Consequences of the variations of the concentration of intranuclear free calcium are still to be defined.
On the whole, the calcium concentration in the cytoplasm can increase primarily by influx of extracellular calcium and release of calcium from the sarcoplasmic reticulum. It is admitted that these two mechanisms act in a complementary way: the extracellular calcium penetration inside the cytoplasm triggers the efflux of calcium from the sarcoplasmic reticulum.
This brief description does not take into account the oscillatory exchanges of calcium between the various cellular structures
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