Intracellular calcium - Role
The variations of the concentration of intracellular Ca2+ are involved in the initiation of electric and mechanical phenomena: depolarization, contraction of smooth and striated muscles, hormonal secretion, activation of enzymes such as A2 phospholipase or various proteases.
- At the level of the heart:
Slow diastolic depolarization is at the origin of the cardiac automaticity. The mechanism of this depolarization, still poorly understood, could be sodium and calcium influx and inhibition of the potassium efflux.
Phase 0 of depolarization is more or less fast according to tissue considered:
- at the level of the sinus and atrioventricular nodes, it is slow and corresponds primarily to calcium influx.
- at the level of the conducting tissue such as the bundle of His, it is faster and corresponds especially to sodium influx.
- At the level of neurons:
The T or N type channels through which calcium enters into neurons take part in their depolarization.
The increase in the calcium concentration is at the origin of muscular contraction and its decrease of relaxation. However the transfers of calcium differ according to the nature of the muscles: cardiac striated muscle, skeletal striated muscle, vascular smooth muscle.
- In the contraction of cardiac striated muscle the influx of extracellular Ca2+ through channels of the plasma membrane and its release by the sarcoplasmic reticulum are involved simultaneously. The variation of the myocardial concentration of Ca2+ during the cardiac revolution illustrates the speed and the importance of the exchanges: it is approximately 10 times higher during the systole than during the diastole.
Extracellular calcium penetrates into the cell during phase 2 or the plateau of the action potential. The voltage-gated calcium channels contribute to the rise in the intracytoplasmic calcium concentration of myocardial fibers. This increase elicits a reinforcement of their contraction.
The inhibition of the calcium influx by calcium antagonists can elicit a negative inotropic effect.
The rise in the concentration of intracellular cAMP, by inducing phosphorylation of the voltage-dependant calcium channels, tends to increase the calcium influx. Cyclic AMP increases moreover the active uptake of calcium by the sarcoplasmic reticulum, which decreases the duration of the contraction.
- In the contraction of the skeletal striated muscles, it is the intracellular calcium release and its reuptake by the sarcoplasmic reticulum which play the essential part; this is one of the explanations of the absence of effect of calcium antagonists on the skeletal striated muscles.
Calcium increases the force of contraction while raising the inhibiting effect of troponin: in the presence of calcium, troponin conformation changes and releases actin, which interacts with phosphorylated myosin.
- In the contraction of smooth muscles, the penetration of extracellular calcium plays a part more important than its release from the sarcoplasmic reticulum.
Their contraction is, in addition, independent of the sodium channels whose inhibition by tetrodotoxin is without effect.
At the level of smooth vascular muscle, calcium acts primarily via calmodulin. Calcium combines with calmodulin and the complex calcium-calmodulin activates the MLCK (myosin light chain kinase) by forming with it a ternary complex. This complex transforms myosin into phosphorylated myosin which combines with actin, inducing a contraction of smooth muscle fibers. The Ca2+ / calmodulin complex activates various other enzymes.
The rise of cAMP in smooth muscles has an opposite effect to that of calcium, because it transforms the MLCK, inactive but activable, into phosphorylated MLCK which cannot combine with calmodulin for phosphorylate myosin. However it is the phosphorylated myosin which, while binding to actin with release of energy from ATP transformed into ADP, elicits the muscular contraction. Antagonist of calmodulin are under study.
Calcium is involved in the migration of intracellular organelles: receptors, vesicles. It plays a determining part in secretions and exocytosis.
Modulation of enzyme activity
- Cytoplasmic enzymes
Calcium activates various protein kinases, such as protein kinase C, calmodulin, calpain which hydrolyzes many proteins, A2 phospholipase…
- Mitochondrial e nzymes
Increase of intramitochondrial calcium activates deshydrogenases responsible for the transformation of acetate into pyruvate, of isocitrate into alpha-cétoglutarate and a-cétoglutarate into succinyl-CoA. In a word, the increase in intramitochondrial calcium activates the Krebs cycle and the formation of NADH and increases the synthesis of ATP. The drugs which increase intra-mitochondrial calcium concentration, by inhibiting for example the mitochondrial Na2+/Ca2+ exchanger could have a beneficial effect in certain cardiomyopathies.
- Nuclear enzymes
Changes of intranuclear calcium modulate the activity of various enzymes like endonucleases.
It also is involved via calmodulin in the activation of the cell cycle.
Calcium is essential for the function of the cell and for its replication but its excess has harmful effects. Thus, during the oxydative stress or following overstimulation of the glutamate receptors, the increase in intracellular Ca2+ induces a hypercontracture of the striated or smooth muscles, hyperactivation of enzymes such as phospholipases and especially endonucleases which, through damaging DNA, take part in apoptosis.