Information

Calcium levels and nerve hyperexcitation


Why does lower blood calcium levels (or lower calcium levels in ECF) cause nervous hyperexcitaton? Why does it cause over stimulation of nerves and muscles and spasmic contractions of muscles?
This is why undersecretion of parathormone causes parathyroid tetany.
I am aware of the role of calcium in opening the synaptic vesicles for transmission of impulses and the role of calcium in muscle contraction but fail to understand how that might hep me understand the overexcitation of nerves and spasmic contraction of muscles. It actually seems that higher calcium in ECF might cause over stimulation and spasms of muscles due to sustained contraction.


From Uptodate on Clinical Manifestations of Hypocalcemia:

Acute hypocalcemia directly increases peripheral neuromuscular irritability [ 1 ]. As measured electromyographically, tetany consists of repetitive high-frequency discharges after a single stimulus. Hyperexcitability of peripheral neurons is probably the most important pathophysiologic effect of hypocalcemia, but hyperexcitability occurs at all levels of the nervous system, including motor end-plates, the spinal reflexes, and the central nervous system.

Guyton and Hall Textbook of Physiology:

The concentration of calcium ions in the extracellular fluid also has a profound effect on the voltage level at which the sodium channels become activated. When there is a deficit of calcium ions, the sodium channels become activated (opened) by very little increase of the membrane potential from its normal, very negative level. Therefore, the nerve fiber becomes highly excitable, sometimes discharging repetitively without provocation rather than remaining in the resting state. In fact, the calcium ion concentration needs to fall only 50 per cent below normal before spontaneous discharge occurs in some peripheral nerves, often causing muscle “tetany.”This is sometimes lethal because of tetanic contraction of the respiratory muscles.

The probable way in which calcium ions affect the sodium channels is as follows:These ions appear to bind to the exterior surfaces of the sodium channel protein molecule. The positive charges of these calcium ions in turn alter the electrical state of the channel protein itself, in this way altering the voltage level required to open the sodium gate.


It is a question of transmembrane potential. Ca++ being a cation, means that if you decrease the amount of ionized calcium in the extra cellular fluid, it conceptually is nearly equivalent to having a more positively charged intracellular fluid. This in turn means that the cell will be closer to its threshold potential for depolarization, therefore accounting for its hyper excitability.

What you should keep in mind, is that when we say something as: "this cell has a transmembrane potential of -70 mV", we always define it relatively to the extra cellular fluid.

Edit: I am leaving this incorrect answer because of the interesting comments below.


Calcium signaling

Calcium signaling is the use of calcium ions (Ca 2+ ) to communicate and drive intracellular processes often as a step in signal transduction. Ca 2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins. Ca 2+ can act in signal transduction resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.


Calcium is initial trigger in our immune response to healing

For the first time scientists studying the cellular processes underlying the body's response to healing have revealed how a flash of calcium is the very first step in repairing damaged tissue. The findings, published in Current Biology, could lead to new therapies that speed up the healing process following injury or surgery.

Until recently, very little was known about how damaged tissue activates and attracts the first white blood cells to the wound -- the first stage in the healing process. However, researchers from the University of Bristol's School of Biochemistry in collaboration with a team from the University of Bath, have shown that the very first trigger in this process is a flash of calcium which spreads like a wave back from the wound edge through gap junctions that connect all the cells.

This flash of calcium signal goes on to activate an enzyme known as DUOX that synthesises hydrogen peroxide, which, in turn, attracts the first white blood cells to the wound. This white blood cell invasion, which is initiated during our inflammatory responses, is needed to kill off invading microbes and stop the onset of septicaemia following tissue damage.

The findings indicate that the wound-induced calcium flash represents the earliest identified signal following wounding and might therefore orchestrate the rapid recruitment of immune cells.

To assess the impact of a reduced calcium flash upon the inflammatory response the team used Drosophila (fruit fly) embryos because they are translucent which makes it easy to image the inflammatory response and because of their simple genetics. The team found that blocking the calcium flash inhibited H2O2 release at the wound site leading to a reduction in the number of immune cells migrating to the wound.

Paul Martin, Professor of Cell Biology and an expert in wound healing at the University, said: "White blood cells are a little like 'Jeckyll and Hyde' in that they help us heal but are also the reason behind why we scar so we really need to know how they are regulated at wounds in order to learn how to control their behaviours for future therapeutic intervention."

Will Razzell, the lead PhD researcher on this study, added: "We are more than ever understanding the pathways that lead to immune cell attraction to wounds. As calcium represents the immediate inflammatory signal, we now have a good foundation to investigate this complicated process further."


Hormonal Control of Blood Calcium Levels

Regulation of blood calcium concentrations is important for generation of muscle contractions and nerve impulses, which are electrically stimulated. If calcium levels get too high, membrane permeability to sodium decreases and membranes become less responsive. If calcium levels get too low, membrane permeability to sodium increases and convulsions or muscle spasms may result.

Blood calcium levels are regulated by parathyroid hormone (PTH), which is produced by the parathyroid glands. PTH is released in response to low blood calcium levels. It increases calcium levels by targeting the skeleton, the kidneys, and the intestine. In the skeleton, PTH stimulates osteoclasts, which are cells that cause bone to be reabsorbed, releasing calcium from bone into the blood. PTH also inhibits osteoblasts, cells which deposit bone, reducing calcium deposition in bone. In the intestines, PTH increases dietary calcium absorption and in the kidneys, PTH stimulates re-absorption of the calcium. While PTH acts directly on the kidneys to increase calcium re-absorption, its effects on the intestine are indirect. PTH triggers the formation of calcitriol, an active form of vitamin D, which acts on the intestines to increase absorption of dietary calcium. PTH release is inhibited by rising blood calcium levels.

Figure (PageIndex<1>): Regulation of blood calcium levels: Parathyroid hormone (PTH) is released in response to low blood calcium levels. It increases blood calcium levels by stimulating the resorption of bones, increasing calcium resorption in the kidneys, and indirectly increasing calcium absorption in the intestines.

Hyperparathyroidism results from an overproduction of PTH, which leads to excessive amounts of calcium being removed from bones and introduced into blood circulation. This may produce structural weakness of the bones, which can lead to deformation and fractures, plus nervous system impairment due to high blood calcium levels. Hypoparathyroidism, the underproduction of PTH, results in extremely low levels of blood calcium, which causes impaired muscle function and may result in tetany (severe sustained muscle contraction).

The hormone calcitonin, which is produced by the parafollicular (or C) cells of the thyroid, has the opposite effect on blood calcium levels as PTH. Calcitonin decreases blood calcium levels by inhibiting osteoclasts, stimulating osteoblasts, and stimulating calcium excretion by the kidneys. This results in calcium being added to the bones to promote structural integrity. Calcitonin is most important in children (when it stimulates bone growth), during pregnancy (when it reduces maternal bone loss), and during prolonged starvation (because it reduces bone mass loss). In healthy, nonpregnant, unstarved adults, the role of calcitonin is unclear.


Electrolytes

Electrolytes are essential for basic life functioning, such as maintaining electrical neutrality in cells, generating and conducting action potentials in the nerves and muscles. Sodium, potassium, and chloride are the significant electrolytes along with magnesium, calcium, phosphate, and bicarbonates. Electrolytes come from our food and fluids.

These electrolytes can have an imbalance, leading to either high or low levels. High or low levels of electrolytes disrupt normal bodily functions and can lead to even life-threatening complications. This article reviews the basic physiology of electrolytes and their abnormalities, and the consequences of electrolyte imbalance.

Sodium, which is an osmotically active anion, is one of the most important electrolytes in the extracellular fluid. It is responsible for maintaining the extracellular fluid volume, and also for regulation of the membrane potential of cells. Sodium is exchanged along with potassium across cell membranes as part of active transport.

Sodium regulation occurs in the kidneys. The proximal tubule is where the majority of the sodium reabsorption takes place. In the distal convoluted tubule, sodium undergoes reabsorption. Sodium transport takes place via sodium-chloride symporters, which is by the action of the hormone aldosterone.

Among the electrolyte disorders, hyponatremia is the most frequent. Diagnosis is when the serum sodium level less than 135 mmol/L. Hyponatremia has neurological manifestations. Patients may present with headache, confusion, nausea, deliriums. Hypernatremia presents when the serum sodium levels greater than145 mmol/L. Symptoms of hypernatremia include tachypnea, sleeping difficulty, and feeling restless. Rapid sodium corrections can have serious consequences like cerebral edema and osmotic demyelination syndrome.

Potassium is mainly an intracellular ion. The sodium-potassium adenosine triphosphatase pump has the primary responsibility for regulating the homeostasis between sodium and potassium, which pumps out sodium in exchange for potassium, which moves into the cells. In the kidneys, the filtration of potassium takes place at the glomerulus. The reabsorption of potassium takes place at the proximal convoluted tubule and thick ascending loop of Henle. Potassium secretion occurs at the distal convoluted tubule. Aldosterone increases potassium secretion. Potassium channels and potassium-chloride cotransporters at the apical membrane also secrete potassium.

Potassium disorders are related to cardiac arrhythmias. Hypokalemia occurs when serum potassium levels under 3.6 mmol/L—weakness, fatigue, and muscle twitching present in hypokalemia. Hyperkalemia occurs when the serum potassium levels above 5.5 mmol/L, which can result in arrhythmias. Muscle cramps, muscle weakness, rhabdomyolysis, myoglobinuria are presenting signs and symptoms in hyperkalemia.

Calcium has a significant physiological role in the body. It is involved in skeletal mineralization, contraction of muscles, the transmission of nerve impulse, blood clotting, and secretion of hormones. The diet is the predominant source of calcium. It is mostly present in the extracellular fluid. Absorption of calcium in the intestine is primarily under the control of the hormonally active form of vitamin D, which is 1,25-dihydroxy vitamin D3. Parathyroid hormone also regulates calcium secretion in the distal tubule of kidneys. Calcitonin acts on bone cells to increase the calcium levels in the blood.

Hypocalcemia diagnosis requires checking the serum albumin level to correct for total calcium, and the diagnosis is when the corrected serum total calcium levels are less than 8.8 mg/dl, as in vitamin D deficiency or hypoparathyroidism. CHecking serum calcium levels is a recommended test in post-thyroidectomy patients. Hypercalcemia is when corrected serum total calcium levels exceed 10.7 mg/dl, as seen with primary hyperparathyroidism. Humoral hypercalcemia presents in malignancy, primarily due to PTHrP secretion.

The acid-base status of the blood drives bicarbonate levels. The kidneys predominantly regulate bicarbonate concentration and are responsible for maintaining the acid-base balance. Kidneys reabsorb the filtered bicarbonate and also generate new bicarbonate by net acid excretion, which occurs by excretion of both titrable acid and ammonia. Diarrhea usually results in loss of bicarbonate, thus causing an imbalance in acid-base regulation.

Magnesium is an intracellular cation. Magnesium is mainly involved in ATP metabolism, contraction and relaxation of muscles, proper neurological functioning, and neurotransmitter release. When muscle contracts, calcium re-uptake by the calcium-activated ATPase of the sarcoplasmic reticulum is brought about by magnesium. Hypomagnesemia occurs when the serum magnesium levels are less under 1.46 mg/dl. It can present with alcohol use disorder and gastrointestinal and renal losses—ventricular arrhythmias, which include torsades de pointes seen in hypomagnesemia.

Chloride is an anion found predominantly in the extracellular fluid. The kidneys predominantly regulate serum chloride levels. Most of the chloride, which is filtered by the glomerulus, is reabsorbed by both proximal and distal tubules (majorly by proximal tubule) by both active and passive transport.

Hyperchloremia can occur due to gastrointestinal bicarbonate loss. Hypochloremia presents in gastrointestinal losses like vomiting or excess water gain like congestive heart failure.

Phosphorus is an extracellular fluid cation. Eighty-five percent of the total body phosphorus is in the bones and teeth in the form of hydroxyapatite the soft tissues contain the remaining 15%. Phosphate plays a crucial role in metabolic pathways. It is a component of many metabolic intermediates and, most importantly of adenosine triphosphate(ATPs) and nucleotides. Phosphate is regulated simultaneously with calcium by Vitamin D3, PTH, and calcitonin. The kidneys are the primary avenue of phosphorus excretion.

Phosphorus imbalance may result due to three processes: dietary intake, gastrointestinal disorders, and excretion by the kidneys.


Circadian modulation of calcium levels in cells in the suprachiasmatic nucleus

There is reason to believe that resting free calcium concentration [Ca2+]i in neurons in the suprachiasmatic nucleus (SCN) may vary with the circadian cycle. In order to start to examine this hypothesis, optical techniques were utilized to estimate resting Ca2+ levels in SCN cells in a rat brain slice preparation. [Ca2+]i measured from the soma was significantly higher in the day than in the night. Animals from a reversed light-dark cycle were used to confirm that the phase of the rhythm was determined by the prior light-dark cycle. The rhythm in Ca2+ levels continued to be expressed in tissue collected from animals maintained in constant darkness, thus confirming the endogenous nature of this variation. Interestingly, the rhythm in Ca2+ levels was not observed when animals were housed in constant light. Finally, the rhythm in Ca2+ levels was prevented when slices were exposed to tetrodotoxin (TTX), a blocker of voltage-sensitive sodium channels. Similar results were obtained with the voltage-sensitive Ca2+ channel blocker methoxyverapamil. These observations suggest a critical role for membrane events in driving the observed rhythm in Ca2+. Conceptually, this rhythm can be thought of as an output of the circadian oscillator. Because [Ca2+]i is known to play a critical role in many cellular processes, the presence of this rhythm is likely to have many implications for the cell biology of SCN neurons.

Figures

Neurons in SCN brain slices…

Neurons in SCN brain slices visualized by IR DIC video microscopy. Left: image…

SCNcells in brain slice loaded…

SCNcells in brain slice loaded with the Ca 2+ indicator dye fura2. Left:…


Nerves

Sensory receptors – specialised cells that can detect changes in our surroundings. They are energy transducers that convert one form of energy to another. A transducer is adapted to detect changes in a particular form of energy.

Stimulus – a change in energy levels in the environment. Whatever the stimulus the sensory receptors convert the energy into a form of electrical energy called nerve impulse.

  • describe, with the aid of diagrams, the structure and functions of sensory and motor neurones

There is a number of different neurones, including:

  • Sensory neurone – carry action potentials from a sensory receptor to the central nervous system.
  • Relay neurone – connect sensory and motor neurones.
  • Motor neurone – carry action potentials from the central nervous system to an effector, e.g. muscle or gland.

Resting potential– the potential difference or voltage across the neurone cell membrane while the neurone is at rest. It is about -60mV inside the cell compared with the outside. The membrane is said to be polarised.

  1. The sodium-potassium pumps in the membrane of the axon continually pump 3Na + ions out the cell for every 2 K + ionsmoved into the cell against a concentration gradient, using energy provided by a large number of mitochondria found in the neurone.
  2. Due to the concentration gradients, Na +ions tend to leak back into the cell, and K +ions tend to leak out.
  3. K + ions leaks out at a faster rate (1.5 times) than the rate of Na + ionsleaking back in, meaning that there are more positive ions (cations) outside the cell than inside the cell, and more negative ions (anions) in the cytoplasm.
  4. This all results in a potential difference of -60mV between the inside and outside of the cell. The difference is called the resting potential. The axon membrane is said to be polarised when it is in this state.
  • describe and explain how an action potential is generated

Action potential– the depolarisation of the cell membrane so that the inside is more positive than the outside, with a potential difference across the membrane of +40mV.

  1. A stimulus causes sodium ion channels in the axon membrane to open, allowing Na + ions to move into the cell, down an electro-chemical gradient (more positive to more negative).
  2. The movement of Na + ions increases the potential difference resulting in voltage-dependent gates opening, which allow even more Na + ions in. The large number of positive ions cause the potential difference to rise to +40mV.
  3. The sodium ion channels close and the potassium ions channels open, allowing K + ions to move out of the cell, to try to restore the balance of charges either side of the membrane – this is repolarisation.
  4. So many K + ionsleave the cell causing the potential difference to drop below the –60mV (called hyperpolarisation), which causes the potassium ions channels to close.
  5. The membrane’s sodium-potassium pumps will quickly restore the potential difference to the normal resting potential figure of -60mV.

Refractory period– the short time when the membrane is hyperpolarised. In this time it is impossible to stimulate the cell membrane to reach another action potential.

Threshold potential– The potential difference across the membrane of about –55mV. If the depolarisation of the membrane does not reach the threshold potential then no action potential is created.

    describe and explain how an action potential is transmitted in a myelinated neurone, with reference to the roles of voltage-gated sodium ion and potassium ion channels

  1. When an action potential occurs, the sodium ion channels open at a particular point along the neurone, allowing Na + ions to diffuse across the membrane from high concentration outside the neurone to low concentration inside the neurone.
  2. The movement of Na + ions into the neurone upsets the balance of ionic concentrations created by the sodium-potassium pumps.
  3. The concentration of sodium ions inside the neurone rises at the point where the sodium ion channels are open, causing the Na + ions to diffuse sideways, away from this region of increased concentration.
  4. This is called a local current – the movements of ions along the neurone. The flow of ions is caused by an increase in concentration at one point, which causes diffusion away from the region of higher concentration.

The myelin sheath is an insulating layer of fatty material, made of Schwann cells, which is impermeable to Na + and K + ions. Therefore, the ionic movements that create an action potential cannot occur at the parts of axon with the myelin sheath. Instead, the action potentials only occur between the Schwann cells. These gaps are called nodes of Ranvier. The action potentials appear to jump from one node to the next. This is called saltatory conduction. This speeds up the transition of the action potential. Myelinated neurones conduct action potentials more quickly than non-myelinated neurones.

Saltatory conduction‘jumping conduction’ refers to the way that the action potential appears to jump from one node of Ranvier to the next.

    interpret graphs of the voltage changes taking place during the generation and transmission of an action potential

  1. The neurone is at resting state (-60mV) and the membrane is said to be polarised.
  2. A stimulus causes sodium ion channels to open and Na + ions move intothe cell causing the membrane potential to increase to the threshold potential (-55mV).
  3. The membrane becomes depolarised and the cell becomes positively charged inside compared to outside.
  4. The membrane potential reaches +40mV. The sodium ion channels close and the potassium ion channels open and K + ions diffuse out of the cell.
  5. The membrane becomes repolarised as the potential difference goes back to negative inside compared with outside.
  6. The membrane becomes hyperpolarised as the potential difference overshoots slightly from too many K + ions move out the cell.
  7. The original potential difference is restored so that the cell returns to its resting state.

When a stimulus is at a higher intensity the sensory receptor will produce more generator potentials. This will cause more frequent action potentials in the sensory neurone. When these arrive at the synapse they will cause more vesicles to be released. Therefore this creates a higher frequency of action potentials in the postsynaptic neurone. Our brain can determine the intensity of the stimulus from the frequency of signals arriving. A higher frequency of signals means a more intense stimulus.

Summation – refers to the way that several small potential changes can combine to produce one larger change in potential difference across the membrane.

Low-level signals can be amplified by a process called summation:

  • Temporal summation
  • If a low-level stimulus is persistent it will generate severalaction potentials in the presynaptic neurone releasing many vesicles which will produce an action potential in the postsynaptic neurone.
  • Several impulses arriving at the same neurone via the samesynapse.
  • Spatial summation
  • Several presynaptic neurones each release small numbersof vesicles into one postsynaptic neurone.
  • Several impulses arriving at the same neurone via severalsynapses.

Synapse – the junction between two or more neurones, where neurones can communicate with, or signal to, another neurone.

Cholinergic synapse – those that use acetylcholine as their transmitter substance.

Neurotransmitter – this is the transmitter substance which is a chemical released by the presynaptic neurone, that diffuses across the synaptic cleft (the gaps between two neurones) to transmit a signal to the postsynaptic neurone.

· many mitochondria – indicating active processes that need ATP.

· large amount of smooth endoplasmic reticulum present.

· vesicles of a chemical called acetylcholine – the transmitter substance that will diffuse across the synaptic cleft.

  • outline the role of neurotransmitters in the transmission of action potentials
  1. An action potential arrives at the presynaptic neurone. The voltage-gated calcium ion channels open and Ca + ionsdiffuse into the synaptic knob.
  2. The Ca + ions causes the vesicles containing acetylcholine to moveto and fuse with the presynaptic membrane. Acetylcholine is released by exocytosis.
  3. Acetylcholine diffuse across the synaptic cleft and they bind to the receptor sites on the sodium ion channels in the postsynaptic neurone, causing the sodium ion channels to open. Na + ions diffuse across the membrane and move intothe postsynaptic neurone and an action potential is created.
  4. Acetylcholinesterase, found in the synaptic cleft, hydrolyses acetylcholine to ethanoic acid and choline so that they can be recycled and to stop the action potential in the postsynaptic neurone. Ethanoic acid and cholinere-enter the presynaptic knob by diffusion and are recombined to acetylcholine using ATP from respiration in the mitochondria.

The main role of synapses is to connect two neurones together so that a signal can be passed from one to the other. Other functions include:


Nerve Cell

Nerve cells which are also called neurons are the cells of the nervous system. They are present in almost all animals but not present in fungi and plants. Nerve cells are electrically excitable cells. They receive information from the environment and allows the effector glands to respond to the stimuli. Neurons are present abundantly in the body. A single human body contains an average of almost 86 billion nerve cells. Nerve cells are also the longest cells of our body.

Motor neurons which are also called motoneurons carry the information from the brain and spinal cord to the effector muscles and glands. The cell body of a motor neuron is located in the brainstem or spinal cord and the axon projects to the spinal cord or outside the spinal cord. Motor neurons are of two types, upper motor neurons, and lower motor neurons.

Upper motor neurons make connections with interneurons in the spinal cord. Axons of lower motor neurons carry information from the spinal cord to effector muscles or glands. It is important to note that a single motor neuron may innervate more than one muscle fiber.

Motor neurons and muscle fibers are connected through a specialized synapse called the neuromuscular junction. When motor neurons are stimulated, they release acetylcholine which binds to postsynaptic receptors. Ion channels are opened, and an influx of sodium triggers a muscle action potential and the target muscle fiber contracts.

Interneurons are also called association neurons, relay neurons, or intermediate neurons. They make communication between motor neurons and sensory neurons. Interneurons are known to play an important role in neurogenesis, reflexes, neuronal oscillations. Interneurons are divided into two groups, local interneurons, and relay interneurons.

Local interneurons have relatively short axons. Their function is to analyze the information that comes from the sensory neurons. On the other side, the relay interneurons have longer axons than local interneurons. They connect the circuits of neurons in different regions of the brains. The interaction between interneurons is necessary for the learning and decision-making process of the brain.

Some interneurons use the neurotransmitter GABA or glycine which are inhibitory neurotransmitters. Some other interneurons are excitatory because they use glutamate and acetylcholine as neurotransmitters. The main function of interneurons is to connect the motor and sensory neurons and conduct a flow of signals between them.


Hormones and Osmoregulation: Endocrine Involvement in Calcium Regulation in Teleosts

J.C. Fenwick , S.E. Wendelaar Bonga , in Invited Lectures , 1982

CALCIUM HOMEOSTASIS IN MAMMALS

Calcium homeostasis in mammals, as in other tetrapods, appears to be dominated by the fact that these animals rely on their food and drink for the calcium they require, and that they eat and drink only at intervals. As such, they have but intermittent access to calcium and this poses two problems. Firstly, during absorption of ingested calcium the animal must limit the postprandial hypercalcemia which could result from excessively rapid calcium absorption. Secondly, as ingestion of calcium is intermittent, there must be some premium placed on calcium storage during those times when calcium is available in order to provide for those periods when external calcium is not available.

In mammals, the regulatory requirements are met predominantly by the interaction of three hormones, the vitamin D3 complex, parathyroid hormone (PTH) and calcitonin, which act primarily on three target organs: intestinal mucosa, kidney and bone. As several recent reviews ( Copp, 1976 Dacke, 1980 Pang, Kenny and Oguro, 1980 ) give very adequate descriptions of calcium regulation in mammals, we will limit our discussion to a very succinct account of the more important aspects as related to this paper.

The most common perturbation to calcium homeostasis in mammals, as in all tetrapods, is the absorption of ingested calcium from the intestine. Although the rate at which this occurs is under the control of vitamin D dependent uptake mechanisms, the potential exists for the development of elevated plasma calcium levels. This is, however, attenuated by the action of two hormones. As the plasma calcium levels rise, the release of PTH is reduced with a consequent reduction in active bone calcium mobilization. Also, following rising calcium levels, calcitonin is released and inhibits the action of PTH on osteoclastic activity and osteocytic osteolysis ( Luben, Wong and Cohn, 1976 ), enhancing the rate at which the action of PTH is inhibited. As a consequence, the movement of calcium from the blood predominates over the reverse movement and favors the storage of the absorbed calcium in bone. Between periods of intestinal calcium absorption, previously stored calcium is mobilized by the stimulatory action of PTH on bone resorbing cells. We should point out, however, that whilst the concept that bone calcium provides the principal supply of calcium for minute-to-minute regulation of body needs is open to challenge, the bone indisputably functions as an important calcium reservoir during chronic periods of dietary calcium deprivation. Additionally, PTH enhances renal retention of calcium and at the same time seems to stimulate the production of 1,25-dihydroxy vitamin D3, in order to prepare the intestinal mucosa for the next calcium load or to increase the efficiency of the intestinal mucosa to extract calcium from the intestinal contents.


Researchers find trigger that leads to faster nerve healing

University of South Carolina scientists are exploring ways to make nerve regeneration happen faster and more successfully.

A new study published in Current Biology identifies the biological triggers that promote quicker nerve regeneration. From their previous studies, the researchers knew that damaged nerves regrow more quickly when "stress granules" in the site of the nerve injury are broken apart. Now they know what causes those stress granules to disassemble through a process called protein phosphorylation.

"The important thing is that we identified the protein that drives that process and showed how that's regulated," Jeff Twiss, a UofSC biology professor and co-author on the paper, said.

"It actually opens something new," Pabitra Sahoo, the paper's lead author, said. "In the future, it could help us design molecules that can promote phosphorylation."

Twiss said nerves typically regrow at 1 to 2 millimeters per day, meaning that an adult with nerve damage around their kneecap might require a year to recover as the nerve re-extends back to the foot. Given such a prolonged time to regenerate the nerve, atrophy makes a full recovery difficult.

"Finding ways to speed that up is critical to decreasing the amount of time that a person has loss of function, sensation and movement," said Twiss, the UofSC SmartState Chair in Childhood Neurotherapeutics. "But also, when you allow the nerve to find its way back to the target quicker, you can recover much more function."

Nerve cells contain the protein G3BP1 in clusters known as stress granules. When a nerve is severed, those granules begin to break apart through phosphorylation, a modification that makes G3BP1 become more negatively charged. This process releases mRNAs, important building blocks that the cell can use to build new proteins that extend the nerve. This phosphorylation makes the nerve grow faster, according to research that Sahoo and Twiss's team published in 2018.

The 2020 study took a step back to look for the processes that trigger the phosphorylation, in hopes that the entire process could be accelerated. The researchers determined that an enzyme known as Casein kinase 2-alpha (CK2α) is responsible for breaking up the G3BP1 granules through phosphorylation. When they increased CK2α levels, nerves grew faster, and the cell contained more phosphorylated G3BP1. When they decreased CK2α, the process slowed.

But where does the CK2α come from? The researchers placed a piece of nerve in a test tube, damaged it, and monitored the CK2α levels. Those levels increased, indicating that the damaged nerve synthesizes CK2α on its own at the injury site, rather than receiving it from its cell body. The process seems to be regulated by calcium ions.

These discoveries offer promising areas for further study. The UofSC researchers are already looking at methods for spurring the CK2α synthesis to speed up the nerve growth. Finding that key could lead to advances in medicine that result in faster healing after nerve injuries.