Question

Cytosolic Ca2+ is an important “second messenger”, and is usually maintained at sub-micromolar concentrations. List 3 distinct mechanisms through which the cytosolic concentration of Ca2+ is regulated.

Answer 1

Calcium is a ubiquitous second messenger with wide-ranging physiological roles. These include muscle contraction, neuronal transmission (as in an excitatory synapse), cellular motility (including the movement of flagella and cilia), fertilization, cell growth (proliferation), neurogenesis, learning and memory as with synaptic plasticity, and secretion of saliva.

3 distinct mechanisms are as follows:-

1.Muscle Contractions

Contractions of skeletal muscle fiber are caused due to electrical stimulation. This process is caused by the depolarization of the transverse tubular junctions. Once depolarized the sarcoplasmic reticulm (SR) releases Ca2+ into the myoplasm where it will bind to a number of calcium sensitive buffers. The Ca2+ in the myoplasm will diffuse to Ca2+ regulator sites on the thin filaments. This leads to the actual contraction of the muscle.

Contractions of smooth muscle fiber are dependent on how a Ca2+ influx occurs. When a Ca2+ influx occurs, cross bridges form between myosin and actin leading to the contraction of the muscle fibers. Influxes may occur from extracellular Ca2+ diffusion via ion channels. This can lead to three different results. The first is a uniform increase in the Ca2+ concentration through out the cell. This is responsible for increases in vascular diameters. The second is a rapid time dependent change in the membrane potential which leads to a very quick and uniform increase of Ca2+. This can cause a spontaneous release of neurotransmitters via sympathetic or parasympathetic nerve channels. The last potential result is a specific and localized subplasmalemmal Ca2+ release. This type of release increases the activation of protein kinase, and is seen in cardiac muscle where it causes excitation-concentration coupling. Ca2+ may also result from internal stores found in the SR. This release may be caused by Ryaodine (RYRs) or IP3 receptors. RYRs Ca2+ release is spontaneous and localized. This has been observed in a number of smooth muscle tissues including arteries, portal vein, urinary bladder, ureter tissues, airway tissues, and gastrointestinal tissues. IP3 Ca2+ release is caused by activation of the IP3 receptor on the SR. These influxes are often spontaneous and localized as seen in the colon and portal vein, but may lead to a global Ca2+ wave as observed in many vascular tissues.

2. In Neurons

In neurons, concomitant increases in cytosolic and mitochondrial Ca2+ are important for the synchronization of neuronal electrical activity with mitochondrial energy metabolism. Mitochondrial matrix Ca2+ levels can reach the tens of μM levels, that are necessary for the activation of isocitrate dehydrogenase. Which is one of the key regulatory enzymes of the Krebs cycle.

The ER, in neurons, may serve in a network integrating numerous extracellular and intracellular signals in a binary membrane system with the plasma membrane. Such an association with the plasma membrane creates the relatively new perception of the ER and theme of “a neuron within a neuron.” The ER's structural characteristics, ability to act as a Ca2+ sink, and specific Ca2+ releasing proteins, serve to create a system that may produce regenerative waves of Ca2+ release. These may communicate both locally and globally in the cell. These Ca2+ signals, integrateextracellular and intracellular fluxes, and have been implicated to play roles in synaptic plasticity, memory, neurotransmitter release, neuronal excitability, and long term changes at the gene transcription level. ER stress is also related to Ca2+ signaling and along with the unfolded protein response, can cause ER associated degradation (ERAD) and autophagy.

3. In Fertilization

Ca2+ influx during fertilization has been observed in many species as a trigger for development of the oocyte. These influxes may occur as a single increase in concentration as seen with fish and echinoderms, or may occur with the concentrations oscillating as observed in mammals. The triggers to these Ca2+ influxes may differ. The influx have been observed to occurs via membrane Ca2+ conduits and Ca2+ stores in the sperm. It has also been seen that sperm binds to membrane receptors that lead to a release in Ca2+ from the ER. The sperm has also been observed to release a soluble factor that is specific to that species. This ensures cross species fertilization does not occur. These soluble factors lead to activation of IP3 which causes a Ca2+ release from the ER via IP3 receptors. It has also been seen that some model systems mix these methods such as seen with mammals. Once the Ca2+ is released from the ER the egg starts the process of forming a fused pronucleus.