BCH 403

Biochemistry of kidney

Kidneys are one of the vital organs of the body. They are a pair of organs located in the back of
the abdomen. Each kidney is about 4 or 5 inches long. The kidney is approximately 11–14 cm in
length, 6 cm wide and 4 cm thick.

The asymmetry within the abdominal cavity caused by the liver typically results in the right kidney
being slightly lower than the left, and the left kidney is located slightly more medial than the right.
The left kidney is approximately at the vertebral level, and the right slightly lower. The right kidney
sits just below the diaphragm and posterior to the liver, the left below the diaphragm and posterior
to the spleen. Resting on top of each kidney is an adrenal gland. Each adult kidney weighs between
125 and 170 grams in males and between 115 and 155 grams in females.

Each kidney is divided into three main regions, cortex (outer), medulla (inner), and pelvis (Figure
1). The renal corpuscles are located within the cortex. The nephron which spans the cortex and
medulla is the functional unit of the kidney. Each kidney contains around a million units of
nephrons, each of which is a microscopic filter for blood.

The kidneys' function is to filter the blood. All the blood in our bodies passes through the kidneys
several times a day. The kidneys remove wastes, control the body's fluid balance, and regulate the
balance of electrolytes. As the kidneys filter blood, they create urine, which collects in the kidneys'
pelvis -- funnel-shaped structures that drain down tubes called ureters to the bladder.

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Figure 1: Diagram of the kidney

Legend: 1. Renal pyramid. 2. Interlobular artery. 3. Renal artery. 4. Renal vein. 5. Renal hilum. 6. Renal
pelvis. 7. Ureter. 8. Minor calyx. 9. Renal capsule. 10. Inferior renal capsule. 11. Superior renal capsule.
12. Interlobular vein. 13. Nephron. 14. Minor calyx. 15. Major calyx. 16. Renal papilla 17. Renal column

Functions of kidney

1. ROLE IN HOMEOSTASIS

The primary function of kidneys is homeostasis. It is accomplished by the formation of urine.

During the formation of urine, kidneys regulate various activities in the body, which are concerned

with homeostasis such as:

i. Excretion of Waste Products

Kidneys excrete the unwanted waste products, which are formed during metabolic activities:

a. Urea (the end product of amino acid metabolism)

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b. Uric acid (end product of nucleic acid metabolism)

c. Creatinine (end product of metabolism in muscles)

d. Bilirubin (end product of hemoglobin degradation)

e. Products of metabolism of other substances.

Kidneys also excrete harmful foreign chemical substances such as toxins, drugs, heavy metals

pesticides, etc.

ii. Maintenance of Water Balance

Kidneys maintain the water balance in the body by conserving water when it is decreased and

excreting water when it is excess in the body. This is an important process for homeostasis.

iii. Maintenance of Electrolyte Balance

Maintenance of electrolyte balance, especially sodium is in relation to water balance. Kidneys

retain sodium if the osmolarity of body water decreases and eliminate sodium when osmolarity

increases.

iv. Maintenance of Acid-Base Balance

The pH of the blood and body fluids should be maintained within a narrow range for healthy living.

It is achieved by the function of the kidneys. The body is under constant threat to develop acidosis,

because of the production of a lot of acids during metabolic activities. However, it is prevented by

kidneys, lungs and blood buffers, which eliminate these acids. Among these organs, kidneys play

a major role in preventing acidosis. In fact, kidneys are the only organs, which are capable of

eliminating certain metabolic acids like sulfuric and phosphoric acids.

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2. HEMOPOIETIC FUNCTION

Kidneys stimulate the production of erythrocytes by secreting erythropoietin. Erythropoietin is

an important stimulating factor for erythropoiesis. The kidney also secretes another factor called

thrombopoietin, which stimulates the production of thrombocytes

3. ENDOCRINE FUNCTION

Kidneys secrete many hormonal substances in addition to erythropoietin and thrombopoietin.

Hormones secreted by kidneys

i. Erythropoietin

ii. Thrombopoietin

iii. Renin

iv. 1,25-dihydroxycholecalciferol (calcitriol)

v. Prostaglandins.

4. REGULATION OF BLOOD PRESSURE

Kidneys play an important role in the long-term regulation of arterial blood pressure in two ways:

i. By regulating the volume of extracellular fluid

ii. Through renin-angiotensin mechanism.

5. REGULATION OF BLOOD CALCIUM LEVEL

Kidneys play a role in the regulation of blood calcium levels by activating 1,25

dihydroxycholecalciferol into vitamin D. Vitamin D is necessary for the absorption of calcium

from the intestine

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 FUNCTIONAL UNIT OF KIDNEY (NEPHRON)

Each kidney in the human contains about 1 million nephrons, each capable of forming urine. The

kidney cannot regenerate new nephrons. Therefore, with renal injury, disease, or normal aging,

there is a gradual decrease in nephron number. After age 40, the number of functioning nephrons

usually decreases about 10 percent every 10 years; thus, at age 80, many people have 40 percent

fewer functioning nephrons than they did at age 40. This loss is not life-threatening because

adaptive changes in the remaining nephrons allow them to excrete the proper amounts of water,

electrolytes, and waste products.

Each nephron contains a tuft of glomerular capillaries called the glomerulus, through which large

amounts of fluid are filtered from the blood and a long tubule in which the filtered fluid is

converted into urine on its way to the pelvis of the kidney. The glomerulus contains a network of

branching and anastomosing glomerular capillaries. The glomerular capillaries are covered by

epithelial cells, and the total glomerulus is encased in Bowman’s capsule. Fluid filtered from the

glomerular capillaries flows into Bowman’s capsule and then into the proximal tubule, which lies

in the cortex of the kidney. From the proximal tubule, fluid flows into the loop of Henle, which

dips into the renal medulla. Each loop consists of a descending and an ascending limb. The walls

of the descending limb and the lower end of the ascending limb are very thin and therefore are

called the thin segment of the loop of Henle.

After the ascending limb of the loop has returned partway back to the cortex, its wall becomes

much thicker, and it is referred to as the thick segment of the ascending limb. At the end of the

thick ascending limb is a short segment, which is actually a plaque in its wall, known as the macula

densa. The macula densa plays an important role in controlling nephron function. Beyond the

macula densa, fluid enters the distal tubule, which, like the proximal tubule, lies in the renal cortex.

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This is followed by the connecting tubule and the cortical collecting tubule, which lead to the

cortical collecting duct. The initial parts of 8 to 10 cortical collecting ducts join to form a single

larger collecting duct that runs downward into the medulla and becomes the medullary collecting

duct. The collecting ducts merge to form progressively larger ducts that eventually empty into the

renal pelvis through the tips of the renal papillae. In each kidney, there are about 250 of the very

large collecting ducts, each of which collects urine from about 4000 nephrons (Figure 2).

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Figure 2: Structure of the nephron

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SECRETION OF HORMONES BY KIDNEY

Juxtaglomerular apparatus secretes two hormones:

1. Renin

2. Prostaglandin.

1. Renin

Juxtaglomerular cells secrete renin. Renin is a peptide with 340 amino acids. Along with

angiotensins, rennin forms the renin-angiotensin system, which is a hormone system that plays an

important role in the maintenance of blood pressure. Secretion of renin is stimulated by four

factors:

i. Fall in arterial blood pressure

ii. Reduction in the ECF volume

iii. Increased sympathetic activity

iv. Decreased load of sodium and chloride in macula densa.

Renin-angiotensin system

When renin is released into the blood, it acts on a specific plasma protein called angiotensinogen

or rennin substrate. It is the α2-globulin. By the activity of renin, the angiotensinogen is

converted into a decapeptide called angiotensin I. Angiotensin I is converted into angiotensin II,

which is an octapeptide by the activity of angiotensin-converting enzyme (ACE) secreted from

the lungs. Most of the conversion of angiotensin I into angiotensin II takes place in the lungs.

Angiotensin II has a short half-life of about 1 to 2 minutes. Then it is rapidly degraded into a

heptapeptide called angiotensin III by angiotensinases, which are present in RBCs and vascular

beds in many tissues. Angiotensin III is converted into angiotensin IV, which is a hexapeptide.

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Actions of Angiotensins

Angiotensin I is physiologically inactive and serves only as the precursor of angiotensin II.

Angiotensin II is the most active form. Its actions are:

On blood vessels:

i. Angiotensin II increases arterial blood pressure by directly acting on the blood vessels and

causing vasoconstriction. It is a potent constrictor of arterioles. Earlier, when its other actions were

not found it was called hypertension.

ii. It increases blood pressure indirectly by increasing the release of noradrenaline from

postganglionic sympathetic fibers. Noradrenaline is a general vasoconstrictor.

On adrenal cortex:

It stimulates zona glomerulosa of adrenal cortex to secrete aldosterone. Aldosterone acts on renal

tubules and increases retention of sodium, which is also responsible for the elevation of blood

pressure.

On kidney:

i. Angiotensin II regulates glomerular filtration rate by two ways:

a. It constricts the efferent arteriole, which causes decrease in filtration after an initial increase

b. It contracts the glomerular mesangial cells leading to decrease in surface area of glomerular

capillaries and filtration.

ii. It increases sodium reabsorption from renal tubules. This action is more predominant on

proximal tubules.

On brain:

i. Angiotensin II inhibits the baroreceptor reflex and thereby indirectly increases the blood

pressure. The baroreceptor reflex is responsible for decreasing the blood pressure.

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ii. It increases water intake by stimulating the thirst center

iii. It increases the secretion of corticotropin-releasing hormone (CRH) from the hypothalamus.

CRH, in turn, increases secretion of adrenocorticotropic hormone (ACTH) from the pituitary

iv. It increases secretion of antidiuretic hormone (ADH) from the hypothalamus.

2. Prostaglandin

Extraglomerular mesangial cells of juxtaglomerular apparatus secrete prostaglandin. Prostaglandin

is also secreted by interstitial cells of the medulla called type I medullary interstitial cells

3. Erythropoietin

Endothelial cells of peritubular capillaries in the kidney secrete erythropoietin. The stimulant for

its secretion is hypoxia. Erythropoietin is a glycoprotein with 165 amino acids. Erythropoietin

stimulates the bone marrow and causes erythropoiesis.

4. 1,25-dihydroxycholecalciferol

1,25-dihydroxycholecalciferol is otherwise known as calcitriol or activated vitamin D. It is formed

from cholecalciferol, which is present in the skin and intestine. The cholecalciferol (vitamin D3)

from the skin or intestine is converted into 25-hydroxycholecalciferol in the liver. This, in turn, is

activated into 1,25-dihydroxycholecalciferol by parathormone in the kidney.

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Figure 3: Schematic diagram showing activation of vitamin D.

5. Thrombopoietin

Thrombopoietin is a glycoprotein. It is secreted by the kidneys and liver. Thrombopoietin

stimulates the production of platelets.

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URINE FORMATION

Urine formation is a blood cleansing function. Normally, about 1,300 mL of blood (26% of cardiac

output) enters the kidneys. Kidneys excrete unwanted substances along with water from the blood

as urine. Normal urinary output is 1 L/day to 1.5 L/day.

Properties of urine

Volume : 1,000 to 1,500 mL/day

Reaction: Slightly acidic with a pH of 4.5 to 6

Specific gravity: 1.010 to 1.025

Osmolarity : 1,200 mOsm/L

Color: Normal straw color

Odour: Fresh urine has a light aromatic odor.

If stored for some time, the odour becomes stronger due to bacterial decomposition.

Composition of urine

Urine consists of water and solids. Solids include organic and inorganic substances

Figure 4: Quantity of solids excreted in urine (mMols/day)

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Figure 5: urine secretion

PROCESSES OF URINE FORMATION

When blood passes through glomerular capillaries, the plasma is filtered into the Bowman capsule.

This process is called glomerular filtration. The filtrate from Bowman capsule passes through the

tubular portion of the nephron (Figure 5). While passing through the tubule, the filtrate undergoes

various changes both in quality and quantity. Many wanted substances like glucose, amino acids,

water and electrolytes are reabsorbed from the tubules. This process is called tubular reabsorption.

And, some unwanted substances are secreted into the tubule from peritubular blood vessels. This

process is called tubular secretion or excretion.

Thus, urine formation includes three processes:

A. Glomerular filtration

B. Tubular reabsorption

C. Tubular secretion.

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Among these three processes filtration is the function of the glomerulus. Reabsorption and

secretion are the functions of tubular portion of the nephron.

(a) GLOMERULAR FILTRATION

Glomerular filtration is the process by which the blood is filtered while passing through the

glomerular capillaries by filtration membrane. It is the first process of urine formation. The

structure of filtration membrane is well suited for filtration. Glomerular filtration is called

ultrafiltration because even the minute particles are filtered. But, the plasma proteins are not

filtered due to their large molecular size. The protein molecules are larger than the slit pores present

in the endothelium of capillaries. Thus, the glomerular filtrate contains all the substances present

in plasma except the plasma proteins.

(b) TUBULAR REABSORPTION

Tubular reabsorption is the process by which water and other substances are transported from renal

tubules back to the blood. When the glomerular filtrate flows through the tubular portion of

nephron, both quantitative and qualitative changes occur. A large quantity of water (more than

99%), electrolytes and other substances are reabsorbed by the tubular epithelial cells. The

reabsorbed substances move into the interstitial fluid of renal medulla. And from here the

substances move into the blood in peritubular capillaries. Since the substances are taken back into

the blood from the glomerular filtrate, the entire process is called tubular reabsorption. Tubular

reabsorption is known as selective reabsorption because the tubular cells reabsorb only the

substances necessary for the body. Essential substances such as glucose, amino acids and vitamins

are completely reabsorbed from renal tubule. Whereas the unwanted substances like metabolic

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waste products are not reabsorbed and excreted through urine. Basic transport mechanisms

involved in tubular reabsorption are of two types:

1. Active reabsorption

2. Passive reabsorption.

1. Active Reabsorption

Active reabsorption is the movement of molecules against the electrochemical (uphill) gradient.

It needs the liberation of energy, which is derived from ATP. Substances reabsorbed actively from

the renal tubule are sodium, calcium, potassium, phosphates, sulfates, bicarbonates, glucose,

amino acids, ascorbic acid, uric acid and ketone bodies.

2. Passive Reabsorption

Passive reabsorption is the movement of molecules along the electrochemical (downhill)

gradient. This process does not need energy. Substances reabsorbed passively are chloride, urea

and water.

(c) TUBULAR SECRETION

Tubular secretion is the process by which the substances are transported from blood into renal

tubules. It is also called tubular excretion. In addition to reabsorption from renal tubules, some

substances are also secreted into the lumen from the peritubular capillaries through the tubular

epithelial cells. Potassium is secreted actively by sodium-potassium pump in proximal and distal

convoluted tubules and collecting ducts. Ammonia is secreted in the proximal convoluted tubule.

Hydrogen ions are secreted in the proximal and distal convoluted tubules. Maximum hydrogen ion

secretion occurs in proximal tubule. Urea is secreted in loop of Henle. Thus, urine is formed in

nephron by the processes of glomerular filtration, selective reabsorption and tubular secretion.

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HORMONAL REGULATION OF REABSORPTION

1. Aldosterone

Aldosterone increases sodium reabsorption and increases potassium secretion. Aldosterone,

secreted by the zona glomerulosa cells of the adrenal cortex, is an important regulator of sodium

reabsorption and potassium secretion by the renal tubules. The primary site of aldosterone action

is on the principal cells of the cortical collecting tubule. The mechanism by which aldosterone

increases sodium reabsorption while at the same time increasing potassium secretion is by

stimulating the sodium-potassium ATPase pump on the basolateral side of the cortical collecting

tubule membrane. Aldosterone also increases the sodium permeability of the luminal side of the

membrane. In the absence of aldosterone, as occurs with adrenal destruction or malfunction

(Addison’s disease), there is marked loss of sodium from the body and accumulation of potassium.

Conversely, excess aldosterone secretion, as occurs in patients with adrenal tumors (Conn’s

syndrome) is associated with sodium retention and potassium depletion. Although day-to-day

regulation of sodium balance can be maintained as long as minimal levels of aldosterone are

present, the inability to appropriately adjust aldosterone secretion greatly impairs the regulation of

renal potassium excretion and potassium concentration of the body fluids. Thus, aldosterone is

even more important as a regulator of potassium concentration than it is for sodium concentration.

2. Angiotensin II

Angiotensin II increases sodium and water reabsorption. Angiotensin II is perhaps the body’s most

powerful sodium-retaining hormone. Angiotensin II formation increases in circumstances

associated with low blood pressure and/or low extracellular fluid volume, such as during

hemorrhage or loss of salt and water from the body fluids. The increased formation of angiotensin

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II helps to return blood pressure and extracellular volume toward normal by increasing sodium

and water reabsorption from the renal tubules through three main effects:

3. Antidiuretic Hormone (ADH)

ADH increases water reabsorption. The most important renal action of ADH is to increase the

water permeability of the distal tubule, collecting tubule, and collecting duct epithelia. This effect

helps the body to conserve water in circumstances such as dehydration. In the absence of ADH,

the permeability of the distal tubules and collecting ducts to water is low, causing the kidneys to

excrete large amounts of dilute urine. Thus, the actions of ADH play a key role in controlling the

degree of dilution or concentration of the urine. ADH binds to specific V2 receptors in the late

distal tubules, collecting tubules, and collecting ducts, increasing the formation of cyclic AMP and

activating protein kinases. This, in turn, stimulates the movement of an intracellular protein, called

aquaporin-2 (AQP-2), to the luminal side of the cell membranes. The molecules of AQP-2 cluster

together and fuse with the cell membrane by exocytosis to form water channels that permit rapid

diffusion of water through the cells. There are other aquaporins, AQP-3 and AQP-4, in the

basolateral side of the cell membrane that provide a path for water to rapidly exit the cells, although

these are not believed to be regulated by ADH. Chronic increases in ADH levels also increase the

formation of AQP-2 protein in the renal tubular cells by stimulating AQP-2 gene transcription.

When the concentration of ADH decreases, the molecules of AQP-2 are shuttled back to the cell

cytoplasm, thereby removing the water channels from the luminal membrane and reducing water

permeability.

4. Atrial Natriuretic Peptide

Atrial natriuretic peptide decreases sodium and water reabsorption. Specific cells of the cardiac

atria, when distended because of plasma volume expansion, secrete a peptide called atrial

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natriuretic peptide. Increased levels of this peptide in turn inhibit the reabsorption of sodium and

water by the renal tubules, especially in the collecting ducts. This decreased sodium and water

reabsorption increases urinary excretion, which helps to return blood volume back toward normal.

5. Parathyroid Hormone

Parathyroid hormone increases calcium reabsorption. Parathyroid hormone is one of the most

important calcium-regulating hormones in the body. Its principal action in the kidneys is to

increase tubular reabsorption of calcium, especially in the distal tubules and perhaps also in the

loops of Henle. Parathyroid hormone also has other actions, including inhibition of phosphate

reabsorption by the proximal tubule and stimulation of magnesium reabsorption by the loop of

Henle.

Assignment 001:

Write concisely on tests to assess renal function

Write briefly on kidney diseases

NEUROTRANSMITTERS

Neurotransmitter is a chemical substance or chemical messenger (within brain) that is secreted by

neurons and that allow communication between nerve cells to produce physiological response such

as muscle contraction.

Overview of the nerve cell

The neuron: The neuron is the structural and functional unit of the nervous system (Figure 1).

Neurons do not divide, they must last for a lifetime. They function by the production, propagation

and transfer of nerve impulses.

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The functional components of a neuron consist of:

– The cell body (perikaryon) having the nucleus (karyon) and those organelles that maintain the

cell

– The processes extending from the cell body which consists of axon and dendrites.

• Axon, usually the longest process, which transmits impulses away from the cell body to other

neurons or effector (target) cells such as muscle cells or gland (secretory cells).

• Dendrites, usually the shorter processes that transmit impulses from the periphery (i.e. from

other neurons) towards the cell body.

Figure 1: Structure of typical neuron

Synapses

A synapse is a site of functional contact between neurons that facilitate transmission of impulses

from one (presynaptic) neuron to another (postsynaptic) neuron or effector (target) cells such as

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muscle and gland cells. Thus, a synapse is a site of neuron-to-neuron or neuron-to-effector cell

communication.

A typical synapse contains:

(a) Presynaptic Bouton or Knob

The end of a neuro process is terminated in a bulb-like end called a bouton or presynaptic knob

from which neurotransmitters are released. It consists of synaptic vesicles in which

neurotransmitters are stored (Figure 2).

(b) Synaptic Cleft

There is no actual continuity between one neuron and another, a minute gap exists between them.

The space that separates one neuron from another neuron or effector (target) cell, which the

transmitter must cross is called synaptic cleft (Figure 2).

(c) Postsynaptic Membrane

It is a portion of the plasma membrane of the postsynaptic neuron which contains receptor sites

with which the neurotransmitter interacts (Figure 2).

Figure 2: Structure of typical synapse

CLASSIFICATION OF NEUROTRANSMITTERS

A classification of neurotransmitters based on chemical composition is given in Table 1. All are

synthesized at the nerve ending and packaged into vesicles there.

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Table 1: Classification of most common neurotransmitters and their site of synthesis

Mechanism of release of neurotransmitters

Various stimuli (physical, chemical or electrical) activate neurons from their resting state and

cause them to produce nerve impulses. At rest, a neuron maintains a difference in potential (i.e.

voltage) of about –50 to –80 mV between the inside and outside of its surface membrane. Thus the

cell surface is polarized in respect to the cell interior.

When a nerve impulse reaches the bouton, the voltage reversal across the membrane produced by

the impulse (called depolarization) causes Ca2+ channels to open in the plasma membrane of the

bouton. The influx of Ca2+ from the extracellular space causes the synaptic vesicles to migrate to,

and fuse with the presynaptic membrane, thereby releasing the neurotransmitter into the synaptic

cleft by exocytosis.

The neurotransmitter then diffuses across the synaptic cleft and binds to specific receptors on the

postsynaptic membrane causing Na+ channels in that membrane to open and allowing Na+ to enter

the neuron. The influx of Na+ causes local depolarization in the postsynaptic membrane and

thereby generating a new action potential or nerve impulse. The release of neurotransmitters by

the presynaptic bouton can cause either excitation or inhibition at postsynaptic membrane.

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Excitatory Neurotransmitters

Excitatory neurotransmitters like acetylcholine and serotonin open cation channels, prompting an

influx of Na+ that causes local depolarization in the postsynaptic membrane. This leads to the

initiation of an action potential and generation of a nerve impulse.

Inhibitory Neurotransmitters

Inhibitory neurotransmitters like GABA open anion channels causing Cl – to enter the cell and

hyperpolarize the postsynaptic membrane, making it even more negative so that generation of an

action potential (i.e. making membrane depolarized) becomes more difficult and inhibit the

production of new impulse.

Each CNS neuron, in general, receives thousands of synapse, some excitatory and some inhibitory.

Whether a given neuron will generate an impulse or not depends on the summation of the

excitatory and inhibitory transmitters acting upon its surface at any particular time.

Regulation of action of neurotransmitters

When neurotransmitters serve their function, they must be removed from the synaptic space. The

binding of neurotransmitter to receptor appears to be reversible so that bound transmitter

dissociates from its receptors when the local transmitter concentration falls.

The most common process of removal of the neurotransmitter after its release into the synaptic

cleft is by high affinity reuptake mechanism. In high affinity reuptake mechanism,

neurotransmitters are re-incorporated into the presynaptic vesicles by endocytosis and are available

for recycling. About 80% of the released neurotransmitters are removed by this mechanism. The

remaining 20% of the neurotransmitters are degraded by the enzymes associated with the

postsynaptic membrane. For example, acetylcholinesterase (AChE) degrades acetylcholine into

acetate and choline, catechol-o-methyltransferase (COMT) and monoamine oxidase (MAO)

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degrades norepinephrine. The degradation or reuptake of neurotransmitters is necessary to limit

the duration of stimulation or inhibition of the postsynaptic membrane.

DIFFERENT COMMON NEUROTRANSMITTERS

i. Acetylcholine

The first chemical neurotransmitter identified was acetylcholine. It is a neurotransmitter between

axons and striated muscle at the neuromuscular junction (contact made by the terminal branches

of the axon with muscle). Neurons that synthesize and release acetylcholine are termed cholinergic

neurons.

Acetylcholine is synthesized in neuronal cytoplasm from choline and acetyl-CoA through the

action of choline acetyltransferase (Figure 3). Acetylcholine is then incorporated into synaptic

vesicles and stored therein.

Release and action

Release of acetylcholine in response to an action potential is Ca 2+ dependent, as explained above

in the mechanism of release of neurotransmitter. The released acetylcholine diffuses rapidly across

the synaptic cleft to its receptors on the postsynaptic membrane (muscle membrane) causing

opening of the Na+ channels in the receptor that permits a flux of cations across the membrane.

The consequent entry of Na+ results in depolarization of the muscle membrane and action potential

generated and transmitted along the fiber, resulting in contraction of the muscle.

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Figure 3: Synthesis and hydrolysis of acetylcholine

(ii) Catecholamines

The principal catecholamines are:

Norepinephrine (noradrenaline), epinephrine (adrenaline) and dopamine.

Synthesis

These neurotransmitters are synthesized from phenylalanine and tyrosine. Tyrosine is produced in

the liver from phenylalanine through the action of phenylalanine hydroxylase. Tyrosine is then

transported to catecholamine secreting neurons where a series of reactions convert it to dopamine,

to norepinephrine and finally to epinephrine.

Note that dopamine is a major transmitter in nerves that control voluntary movement. Damage to

these nerves causes Parkinson’s disease which is characterized by tremor and difficulties in

initiating and controlling movement.

Storage and release

After synthesis, catecholamines are stored in synaptic vesicles. Catecholamines undergo Ca 2+

dependent release from synaptic vesicles in response to action potentials. After action, the

catecholamine dissociates from its receptor quickly, causing the duration of the biological response

to be brief.

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Functions of catecholamines

• Catecholamines exhibit peripheral nervous system excitatory and inhibitory effects as well as

respiratory stimulation in the CNS.

The excitatory effects are exerted upon:

– Smooth muscle cells of the vessels that supply blood to the skin and mucous membranes.

– Heart, which leads to an increase in heart rate and force of contraction.

Inhibitory effects, by contrast, are exerted upon smooth muscle cells in the wall of the gut, the

bronchial tree of the lungs, and vessels that supply blood to skeletal muscle.

• In addition to their effects as neurotransmitters, norepinephrine and epinephrine can influence

the rate of metabolism by increasing the rate of glycogenolysis and fatty acid mobilization.

• In the periphery, dopamine causes vasodilatation and it is therefore used clinically to stimulate

renal blood flow and is important in the treatment of renal failure.

• Dopamine found in limbic systems of the brain are involved in emotional responses and memory.

(iii) Serotonin or 5-Hydroxytryptamine

Serotonin also called 5-Hydroxytryptamine (5-HT), is derived from tryptophan. Neurons that

secrete 5-HT are termed serotonergic neurons.

Storage and release

Serotonin is stored in vesicles in the axon terminals of these neurons. It undergoes Ca 2+ dependent

release from synaptic vesicles.

The degradation of serotonin results in the formation of 5-hydroxy indole acetic acid (5-HIAA).

This is a useful marker of excess production of serotonin in diseases such as carcinoid syndrome.

Functions

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Serotonin is involved with a wide range of functions such as platelet aggregation, and smooth

muscle contraction, appetite, mood, hormonal balance, sleep/wake cycles, alertness, sexual

behavior and temperature control.

(iv) GABA (Gamma Aminobutyric Acid)

GABA is an amino acid derivative and is the most abundant inhibitor in the brain. It balances the

brain by inhibiting overexcitation.

Synthesis

GABA is synthesized from glutamate (Figure 4) and stored in vesicles in axon terminals.

Glutamate decarboxylase is present in many nerve endings of the brain as well as in the β-cells of

the pancreas.

Figure 4: Synthesis of GABA

Receptors and action

Neurons that secrete GABA are called GABAergic neurons. GABA exerts its effects by binding

to receptors. Binding of GABA to receptors increases the Cl – conductance from outside to inside

the neuron creating hyperpolarization and decreases nerve excitability.

Functions of GABA

• GABA contributes to motor control, vision and many other cortical functions. Anxiety is also

regulated by GABA. Some drugs that increase the level of GABA in the brain are used to treat

epilepsy and Huntington’s disease.

• GABA also stimulates the anterior pituitary, leading to higher levels of human growth hormone

(HGH) which contributes significantly to muscle growth and also prevents the formation of fat

cells.
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(v) Histamine

Histamine is found mainly in the hypothalamus. It is synthesized from histidine by the reaction

catalyzed by histidine decarboxylase, a pyridoxal phosphate containing enzyme (Figure 5).

Histamine is released from synaptic vesicles by exocytosis and interacts with its receptors.

Figure 5: Histidine metabolism

There are three classes of histamine receptors denoted H1, H2 and H3.

Functions

•Histamine has been shown to control the release of pituitary hormones and play a role in sleep-

wake cycles and food intake.

Degradation

• After its action, it is inactivated metabolically. In contrast to other neurotransmitters, a high

affinity Na+ dependent transport system does not exist in brain. In the brain, histamine undergoes

methylation followed by oxidation to methylimidazole acetate.

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