Biophysical Basis of Physiology and Calcium Signaling Mechanism in Cardiac and Smooth Muscle

By Tetsuya Watanabe

Biophysical Basis of Physiology and Calcium Signaling Mechanism in Cardiac and Smooth Muscle acts as a bridge between physiology and physics by discussing the physiology and calcium signaling mechanism in cardiac and smooth muscle. By exploring the mechanism of the cyclic release of stored Ca^(2+) in the SR or ER, this book covers the cell communication system, including excitable cells, recognizing the most relevant mechanisms of cell communication. Serving as a bridge between physiology and physics, coverage spans the physiology and calcium signaling mechanism in cardiac and smooth muscle, offering insight to physiological scientists, pharmaceutical scientists, medical doctors, biologists and physicists.

• Explores the mechanism of the cyclic release of stored Ca^2+ in the SR or ER
• Provides in-depth coverage of cell communication systems to explain the most relevant mechanisms of cell communication
• Covers the physiology and calcium signaling mechanism in cardiac and smooth muscle

• Language: English
• Publisher: Academic Press
• Release date: Feb 1, 2018
• ISBN: 9780128149515

Tetsuya Watanabe

Dr. Tetsuya Watanabe is the President of Watanabe Institute of Mathematical Biology and Watanabe Clinic of Oral Surgery in Hamamatsu, Japan. He graduated from Kanagawa Dental College and holds a DDS degree in dental medicine. He received Postgraduate Training and Fellowship Appointments and successively Faculty Appointments of Associate and Assistant Professor at the Department of Pharmacology, Medical School, University of Pennsylvania, in Philadelphia, USA. Dr. Watanabe is the recent author of Biophysical Basis of Physiology and Calcium Signaling Mechanism in Cardiac and Smooth Muscle, published by Elsevier/Academic Press in 2018.

Book preview

Watanabe

Chapter 1

Introduction

Abstract

Diffusion occurs wherever electric and concentration gradient exists, while flow may occur wherever pressure gradient exists. The speed of diffusion depends on temperature and the tissue property. The cyclic discharge of stored Ca² + from SR or ER was thought to be a basic source of cardiac and intestinal automaticity. It was considered as a natural diffusion phenomenon and evaluated mathematically using a model of Ca² + diffusion through the leaky channel. The movement of the cytosolic Ca² + level shows a damped harmonic oscillation along the straight line with a negative slope. The HCN channel is called the modulator of cardiac automaticity which may increase and stabilize frequency of action potential in the SA node pacemaker cells by means of the activation elicited from an adequate amount of cyclic AMP. In the intestine, inositol triphosphate (IP3) modulates the discharge of Ca² + from the ER.

Keywords

Diffusion; Transporter; Funny currents; Automaticity; Ca² + oscillation; Na+-Ca² + exchanger; Stabilization of signal; Neuronal communication; Second messengers; Modulator of cardiac automaticity

1.1 Mixing, Dilution, and Diffusion

Mixing and dilution of molecules go spontaneously under constant temperature and pressure. These phenomena can be explained by diffusion. Diffusion is defined as the tendency of molecules or ions to move from its higher concentration area to its lower concentration area along the concentration gradient. The driving force of diffusion is the kinetic energy of molecules given by heat transfer. Continuous collisions among molecules produce the pressure fluctuation and bump them down from the area of a higher concentration along a jerky irregular path. And the greater the difference in concentration, the faster the net diffusion of the molecules becomes. Diffusion will stop when the concentration gradient becomes minimized. Increasing temperature results in faster diffusion by an increasing speed of molecules. If temperature and the concentration gradient are the same, the speed of diffusion depends on electrophysical property of the tissue fluid, the size of diffusible molecules, and viscosity of the fluid. Fick's law of diffusion can explain mixing and dilution of molecules mechanically and gives an idea of the speed of movements of particles toward equilibrium.

1.2 Diffusion Through Channels and Transporters

The cell membranes are made of phospholipids, cholesterol, and proteins. The phospholipid bilayer forms the basic structure of the membrane. This self-orienting property of phospholipids leads the biological membrane into a closed spherical structure and reseals it by itself when torn out. Only gases such as oxygen, carbon dioxide, and nitrogen and small nonpolar lipid soluble molecules can diffuse freely through the phospholipid bilayer membrane along their concentration gradients. Ions and polar molecules cannot diffuse through it. Ions and small polar molecules need channels or transporters which are made of columnar proteins firmly inserted into the phospholipid bilayer. Some channels have two states, open and closed, as seen in ligand-gated ion channels and the voltage-gated channels. Only the open state channels act as pores for the selected ions. On the other hand, a transporter forms an intermediate complex with the solute, and a subsequent conformational change in the transporter causes translocation of the solutes to the other side of the membrane. Passive transport processes require no energy supply. They are designed for diffusion of specified polar molecules such as glucose and amino acids that are too large to go through membrane channels by themselves. Active transport processes are used for ions to diffuse across cell membranes against the electrochemical gradients by means of energy supplied by ATP hydrolysis. Action of Na+-K+ pump is an important example of active transport. Since proteins cannot go through the membrane alone, the cell has a unique mechanism of production of the membrane and secreted proteins, and of their transports in the cell. Messenger RNA and ribosomes meet in the cytosol for translation. When the signal peptide is synthesized, the signal peptide on the ribosome is attached to the endoplasmic reticulum (ER) to complete translation, putting the growing peptide chain in the ER. Vesicles containing the proteins formed in the ER are transported to the Golgi apparatus where they are processed under glycosylation by adding, removing, or modifying glycans. Since every cell has a specific pattern of branching glycans on the surface of a cell, it provides a marker by which approaching cells recognize each other. From the Golgi, vesicles shuttle to the lysosomes or to the cell exterior via exocytosis. In exocytosis, cytoplasmic sides of two membranes fuse and then the area of fusion breaks releasing contents of the vesicle outside. Sudden influx of Ca² + into the cell needs to make the fusion possible. The cell membrane has many kinds of glycoproteins which give not only an extra mechanical strength to the membrane but also make the cell capable to communicate with the other cell.

1.3 Diffusion and Flow

Mixing and dilution of molecules go spontaneously under constant temperature and pressure. These phenomena can be explained by diffusion. Diffusion occurs wherever concentration gradient exists, while flow may occur wherever pressure gradient exists. Diffusion goes continuously in the direction to minimize the concentration gradient until equilibrium is achieved. The speed of diffusion depends on temperature, the size and charge of diffusible molecules, and the tissue property. Diffusion through channels or transporters is called facilitated diffusion. Because of low friction through channels, the flux is faster than that of simple diffusion. If the pressure gradient exists, flow may go in the direction to minimize the gradient until the equilibrium is achieved. The speed of flow does not depend on temperature but resistance of the passage. Magnitude of flow is proportional to pressure change and conversely proportional to resistance.

In the respiratory system when the gas flow stops, diffusion takes over the flow. Most of oxygen is carried as a form of oxyhemoglobin. At high altitudes, oxygen concentration in the blood plasma decreases but a total concentration of oxygen in blood is maintained almost constant since hemoglobin in the blood cell is almost saturated whenever the partial pressure of oxygen is above 70 mmHg. Since oxygen concentration is always higher in the blood of capillaries than in the tissue cells, it diffuses continuously to the cells via the interstitial fluid in one direction. Carbon dioxide is at higher concentrations in the tissue cells and so it diffuses in the opposite direction. The Fick's first law of diffusion is that flux per unit area is proportional to the concentration gradient and temperature, and conversely proportional to the friction of the molecule in the tissue. Fick's principle has been applied to measure cardiac output and cerebral blood flow. The concentration gradient of gases or small nonpolar lipid-soluble molecules in the membrane is mathematically justified. It was found to be linear in the membrane if the concentrations of the both sides of membrane are maintained at different constant values. Pressure difference between the atmospheric pressure and alveoli per air flow through trachea gives the airway resistance. The pressure changes in the air-tight body plethysmograph with a patient sitting in give the alveolar pressure change in the lungs after correlation, which makes the measurement of the airway resistance possible without a cannulation in human.

1.4 Diffusion and Currents

Ions diffuse according to electrochemical gradient through the ion channels in the membrane. Ion diffusion through the membrane causes currents, which can change the electrical potential inside the cell. The channels are made of columnar proteins, and their open and close states are controlled by bonding of the ligand to the receptor on the ion channel protein or by means of the voltage sensor. On the other hand, their open and close states at gap junction in ventricular myocardium and smooth muscle are controlled by connexin 43 phosphorylation. Closing the channels means increasing the friction of molecules in the channel. Opening the channels means decreasing the friction of diffusion.

where I is current, Δ V is potential difference, and R is friction in the tissue.

A decrease in R may increase I, followed by a change in the membrane potential. The changes in the membrane potential are measurable. Analytical observations of the wave patterns of the action potential give a clue which ion goes in or goes out through the membrane. Positive ion influx brings the membrane potential higher, and positive ion efflux brings the membrane potential lower.

1.5 Speed of the Wave of Action Potential in Nerve and Muscle Fibers

The rate of impulse propagation in neuron depends on the axon diameter and degree of myelination. The diffusible molecule in this case is always the solvate of sodium ion surrounded by polar water molecules. Oligodendrocytes in central nerve fibers and Schwan cells in peripheral nerve fibers make myelin sheath and wrap around segments of the axon. It speeds up the propagation of neuronal signals by decreasing the ionic leakiness of axon membrane.

Nerve fibers are classified according to their diameter and the degree of myelination. Somatic sensory and motor fibers are grouped in the A fibers. They have the largest diameter and thick myelin sheaths, and the speed of impulse conduction goes up to 150 m/s. Automatic nervous motor fibers, visceral sensory fibers, and the smaller somatic sensory fibers from the skin such as pain and touch fibers are grouped in the B and C fibers where the conduction speeds are not important. Group B fibers are lightly myelinated with intermediate diameter, and the conduction rate of impulse is about 15 m/s. Group C fibers are unmyelinated and have the smallest diameter. The conduction rate is about 1 m/s.

Since the influx of the sodium ion through the voltage-gated Na+ channel initiates neuronal signal and the solvates of sodium ion diffuse and propagate through the axon, the speed of propagation depends on diameter of the axon and its degree of leakage of the solvate of sodium ion across the membrane. Without renewal of the sodium ion at the next voltage-gated sodium channel, the signal will wither.

Demyelination is the act of demyelinating or the loss of the myelin sheath insulating the nerves. Multiple sclerosis is a demyelinating inflammatory disease of the CNS white matter that displays mononuclear cell infiltration, demyelination, and scarring resulting from immunological attack. The peripheral nervous system is uninvolved. The cause of multiple sclerosis has not been clearly understood. However, it is known that there is the presence of autoantibodies to myelin oligodendrocyte glycoprotein in the CNS plaque tissue. These antibodies may act with pathogenic T cells to produce the cellular pathology of multiple sclerosis [1]. It is considered as an autoimmune disease in which the body's immune system attacks its own tissues. In the case of multiple sclerosis, this immune system malfunction destroys myelin. When myelin degrades, conduction of signals along the nerve can be impaired or lost, and the nerve eventually withers. Symptoms may include numbness or weakness in one or more limbs that typically occurs on one side of your body at a time and partial or complete loss of vision, usually in one eye at a time, often with pain during eye