Homeostasis

Árpád Dobolyi

Laboratory of Molecular and Systems Neurobiology,

Department of Physiology and Neurobiology, Eötvös

Loránd University

Outline of the lecture

1. Internal environment of living organisms,

homeostasis

2. Homeostatic regulations – endocrine system,

hormones

3. Examples of homeostatic regulations not

requiring the nervous system

– Potassium level of blood plasma

– Calcium level of blood plasma

4. Homeostatic regulations – nervous system

– Elements of the nervous system

– Hypothalamus

5. Examples of regulations involving the brain

– Water balance

• Intracellular space was formed by the appearance of cellular organisms

(about 3 billion years ago). Its composition differed from that of the ancient

ocean.

• External environment was the sea whose composition was relatively stable.

Each cell was in interaction with the sea, took up and released substances.

• With the appearance of multicellular organisms, most of the cells are not in

contact with the ocean, but rather the interstitial fluid. This is their internal

environment (Claude Bernard: „milieu intérieur”, ~1840), whose composition

resembles to that of the ancient ocean.

• Subsequently, a circulatory system containing blood developed whose

function is to connect the internal environment of different cells of the organism

with each other and the external environment

The internal environment and its evolutionary origin

Transfer of substances in multicellular organisms

Extracellular fluid

• Body cells are situated in watery internal environment through which life-sustaining exchanges are made

• Extracellular fluid (ECF):

Fluid environment in which the cells live (fluid outside the cells)

– Two components:

• Plasma

• Interstitial fluid

• Intracellular fluid (ICF) - Fluid contained within all body cells

Homeostasis

• Defined as maintenance of a relatively

stable internal environment (Walter

Bradford Cannon, 1932, The Wisdom of

the Body).

- Homeostasis is essential for

survival and function of all

cells

- Does not mean that

composition, temperature, and

other characteristics are

absolutely unchanging

• Interstitial fluid is in interaction with the

blood. Thus, the organisms provide

homeostasis through the regulation of

the composition of the blood.

Suspension of cells in plasma (carrier fluid)

45% Cells

55% Plasma

Formed elements (e.g. cells)

Red cells (erythrocytes) 99%

5x106/mL

White cells (leukocytes)

7x103/mL < 1%

Platelets (thrombocytes)

3x105/mL

Blood composition

Blood composition

• Straw colored clear liquid

• Contains 90% water

• 7% plasma proteins created in liver

confined to bloodstream

albumin maintain blood osmotic pressure

immunoglobulins antibodies bind to foreign

substances called antigens

form antigen-antibody complexes

fibrinogen for clotting

• 2% other substances

Nutrients, electrolytes, gases, hormones, waste products

Blood Plasma

• Red blood cells (R.B.C.)

• White blood cells (W.B.C.)

granular leukocytes

neutrophils

eosinophils

basophils

agranular leukocytes

lymphocytes - T cells, B cells, natural killer cells

(N.K.C)

monocytes

• Platelets (special cell fragments)

Formed Elements of Blood

1. Transport oxygen from lungs to the tissues

(oxyhemoglobin).

2. Transport carbon-di-oxide from tissues to lungs

(carboxyhemoglobin)

3. Hemoglobin acts as a buffer and regulates the

hydrogen ion concentration (acid base balance)

4. Carry the blood group antigens and Rh factor

Functions of red blood cells

Ion concentrations within and outside a

typical mammalian cell

Isoionia: homeostasis of ion concentrations and organic small molecules

Ion concentrations in the blood plasma:

Na+.......143 mmol/l Cl-..........................103 mmol/l

K+.............4 mmol/l HCO3-.. ..................24 mmol/l

Ca++......2,5 mmol/l H2PO4- és HPO4--…1 mmol/l

Mg++.........1 mmol/l

Some organic small compounds:

Glocose….4.5-5.50 mmol/l

Urea........2.5-6.3 mmol/l

Isosmosis: Osmotic pressure of blood plasma: 290 milliosmol/l

Isohidria: H-ion concentration: [H+]=35-40 nmol/l (pH: 7.38-7.42)

Buffer systems: carbonates, phosphates, hemoglobin, plasma proteins

Physical parameters: isovolume, isotermia

Some components of homeostasis

Causes of deviation from homeostasis

• Homeostasis is continually being disrupted by

– External stimuli

• heat, cold, lack of oxygen, pathogens, toxins

– Internal stimuli

• Body temperature

• Blood pressure

• Concentration of water, glucose, salts, oxygen, etc.

• Physical and psychological distresses

• Disruptions can be mild to severe

• If homeostasis is not maintained, death may result

Homeostatic control systems

In order to maintain homeostasis, control system must be able to

– Detect deviations from normal in the internal environment that need to be held within narrow limits

– Integrate this information with other relevant information

– Respond: make appropriate adjustments in order to restore factor to its desired value (set point)

Temperature regulation by thermostat

Temporal change of temperature as a

result of regulation by thermostat

Classification of homeostatic control systems

Based on location:

- Intrinsic controls:

• Local controls that are inherent in an organ

- Extrinsic controls

• Regulatory mechanisms initiated outside an organ

• Accomplished by endocrine and nervous systems

Based on mechanism:

- Feedforward - term used for responses made in anticipation of a

change

- Feedback - refers to responses made after change has been

detected

• Negative: original stimulus reversed

• Positive: original stimulus intensified

Feedback Loop

• Receptor - structures that monitor a controlled condition and detect changes

• Control center - determines next action

• Effector – receives directions from the control center

– produces a response that restores the controlled parameter

Example of negative feedback loop to

control blood glucose concentration

• Blood glucose concentrations rise after a sugary meal (the stimulus), the hormone insulin is released and it speeds up the transport of glucose out of the blood and into selected tissues (the response), so blood glucose concentrations decrease (thus decreasing the original stimulus).

Homeostasis of

blood pressure

• Baroreceptors in walls of blood vessels detect an increase in blood pressure

• Brain receives input and signals blood vessels and heart

• Blood vessels dilate, heart rate decreases

• Blood pressure decreases

Positive feedback during childbirth

• Stretch receptors in walls of uterus send signals to the brain

• Brain induces release of hormone (oxytocin) into bloodstream

• Uterine smooth muscle contracts more forcefully

• More stretch, more hormone, more contraction etc.

• Cycle ends with birth of the baby & decrease in stretch

Outline of the lecture

1. Internal environment of living organisms,

homeostasis

2. Homeostatic regulations – endocrine system,

hormones

3. Examples of homeostatic regulations not

requiring the nervous system

– Potassium level of blood plasma

– Calcium level of blood plasma

4. Homeostatic regulations – nervous system

– Elements of the nervous system

– Hypothalamus

5. Examples of regulations involving the brain

– Water balance

Hormones – organic biologically active compounds of different chemical nature that are produced by the endocrine glands, enter directly into blood and accomplish humoral regulation of the metabolism of compounds and functions on the organism level. Hormonoids (tissue hormones) – compounds that are produced not in glands but in different tissues and regulate metabolic processes on the local level, but some of them (serotonin, acetylcholine) enters blood and regulate processes on the organism level.

Four methods of cell-to-cell communication ranging

from direct to remote communication

Endocrine system

• Endocrine system is composed of a number of glands, which are specialized tissues that produce hormones

• Features of the endocrine system:

1. Endocrine glands have a rich supply of blood

2. Hormones, produced by the endocrine glands are secreted into the bloodstream

3. Hormones travel in the blood to target cells close by or far away from point of secretion

4. Hormone receptors are specific binding sites on the target cell

1. Hypothalamus 2. Pituitary 3. Epiphysis (pineal gland) 4. Thyroid (and parathyroid gland) 5. Thymus 6. Adrenal gland 7. Langergans’ islands of pancreas 8. Sex glands (ovary or testis)

Endocrine glands

Chemical nature of hormones

Examples of

different types of

chemical signals

used for cell-to-cell

communication

Secretion of hormones into the blood

• Peptide and protein hormones are secreted by exocytosis

• Steroid (lipophilic) hormones continuously penetrate the membrane -they are not accumulated in cells -their concentration in blood is determined by the speed of synthesis)

Figure 15-14 Essential Cell Biology (© Garland Science 2010)

Protein and peptide hormones are synthesized into

the endoplasmic reticulum

Functions of different parts of the Golgi apparatus

Constitutive and regulated exocytosis

The mechanism of exocytosis of protein and peptide hormones

Electromicroscopic image of insulin sscretion

Posttranslational modification of peptide hormones

Examples of the position of peptide hormones in the newly synthesized protein chains

Cleavage of prohormones by endopeptidases (prohormon convertases) in the Golgi apparatus

Transport of hormones in blood

• Proteins and peptides – in free state

• Steroid hormones and hormones of thyroid gland – bound

with alpha-globulins or albumins

• Catecholamines – in free state or bound with albumins,

sulphates or glucuronic acid

• Reach the target organs

• Cells have the specific receptors to certain hormone

Hormones act where they have receptors

Target cells

Target cells refer to cells that contain specific receptors (binding sites) for a particular hormone. Once a hormone binds to receptors on a target cell, a series of cellular events unfold that eventually impact gene expression and protein synthesis.

Action of steroid hormones

• Steroid hormones enter through the cell membrane and bind to receptors inside of the target cell

• These hormones may directly stimulate transcription of genes to make certain proteins

• Because steroids work by triggering gene activity, the response is slower than peptide hormones

gene

plasma

membrane ribosome

hormone receptor

steroid hormone

mRNA

(nucleus)

RNA polymerase

DNA

(cytoplasm)

new protein

(extracellular

fluid)

A steroid hormone

diffuses through the

plasma membrane

The hormone binds to a

receptor in the nucleus or to

a receptor in the cytoplasm

that carries it into the nucleus

The hormone–receptor

complex binds to DNA and

causes RNA polymerase to

bind to a nearby promoter

site for a specific gene

RNA polymerase catalyzes

the transcription of DNA into

messenger RNA (mRNA)

The mRNA leaves the

nucleus, then attaches to a

ribosome and directs the

synthesis of a specific protein

product

1

2

3

4

5

nuclear

envelope

Receptors of steroid hormones

Action of protein/peptide

hormones

• Protein/peptide hormones do not enter the cell directly. These hormones bind to receptor proteins in the cell membrane.

• When the hormone binds with the receptor protein, a secondary messenger molecule initiates the cell response

• Protein/peptide hormones often produce fast responses

(cytoplasm)

(nucleus)

peptide or amino acid-derived hormone (first messenger)

(extracellular

fluid)

cyclic AMP- synthesizing enzyme

cyclic AMP

ATP

inactive

enzyme

(second messenger)

active

enzyme

reactant

product

plasma membrane

nuclear

envelope

receptor

The hormone binds to a receptor on the plasma membrane of a target cell

1

The activated enzymes catalyze specific reactions 4

The second messenger activates other enzymes

3

Hormone–receptor binding activates an enzyme that catalyzes the synthesis of a second messenger, such as cyclic AMP

2

Receptors of peptide hormones

Types of membrane-bound receptors

Inactivation of hormones

• Hormones are eventually broken down (metabolized) and/or excreted from the body

• The rate of removal from the circulation is fairly constant for a given hormone

• The length of time it takes to remove half of the amount of hormone from the circulation is the half-life of that hormone.

100%

50%

0% Am

ount of H

orm

one

Time

Hormones are inactivated mainly in liver

Inactive metabolites are excreted mainly with urine

Half-time life

- from several min to 20 min – for the majority of

hormones

- till 1 h – for steroid hormones

- till 1 week – for thyroid hormones

Inactivation of hormones 2

Outline of the lecture

1. Internal environment of living organisms,

homeostasis

2. Homeostatic regulations – endocrine system,

hormones

3. Examples of homeostatic regulations not

requiring the nervous system

– Potassium level of blood plasma

– Calcium level of blood plasma

4. Homeostatic regulations – nervous system

– Elements of the nervous system

– Hypothalamus

5. Examples of regulations involving the brain

– Water balance

Isoionia: homeostasis of ion concentrations and organic small molecules

Ion concentrations in the blood plasma:

Na+.......143 mmol/l Cl-..........................103 mmol/l

K+.............4 mmol/l HCO3-.. ..................24 mmol/l

Ca++......2,5 mmol/l H2PO4- és HPO4--…1 mmol/l

Mg++.........1 mmol/l

Some organic small compounds:

Glocose….4.5-5.50 mmol/l

Urea........2.5-6.3 mmol/l

Isosmosis: Osmotic pressure of blood plasma: 290 milliosmol/l

Isohidria: H-ion concentration: [H+]=35-40 nmol/l (pH: 7.38-7.42)

Buffer systems: carbonates, phosphates, hemoglobin, plasma proteins

Physical parameters: isovolume, isotermia

Some components of homeostasis

Potassium homeostasis

• Blood plasma concentration: 3.6-5.0 mmol/l

• Excretion: 90% kidney, 10% gut

• Causes of low potassium ion level:

- reduced oral intake

- intestinal loss: diarrhea, vomiting

- renal loss: kidney disease

Consequence:

Ki/Ke muscles cannot properly contract

• Causes of high potassium ion level :

- increased potassium intake (combined with kodney disease)

- reduced excretion in kidney (e.g. due to digitalis poisining)

- potassium loss from cells (trauma, hemolysis, cytostatics)

Consequence: :

Elevated excitability of muscles: spasms of sceletal muscles, and cardiac problems

Passive regulation of blood plasma

potassium from „internal store”

Passive control: extracellular K-ion level acts on the activity of Na-K pump and

potassium channels present in the plasmamembrane of all cells. Small relative

change of the intracellular potassium level, which has no effect on intracellular

processes, can significantly compensate the smaller level of potassium in the

extracellular space

Compartments interacting with the blood:

potential surfaces of regulations

• Gastrointestinal tract

- Behaviors determining feeding and drinking

- Regulation of absorption

- Secretion with faces

• Kidney

• Lung (mostly for gases)

• Sweat

• Internal stores

- Binding proteins in the blood

- Intracellular space of the cells

- Organs specialized for storage

Nephron

Reabsorption in the proximal convoluted tubule

Nephron

Reabsorption in the distal convoluted tubule and

the collecting duct

Hormonally regulated active control of blood

potassium ion level

- 92% of potassium ion of the primary urine is

reabsorbed before the collecting duct

- There is a low speed non-controlled potassium ion

reabsorption in the medully, which reabsorbes all

potassium ion leading to zero excretion without

regulation

- Active regulation: aldosterone, a

mineralocorticoid steroid hormone released from the

adrenal gland leads to increased secretion of

potassium in the initial segment of the collecting

duct thereby reducing blood plasma potassium ion

level. This is the only active regulation of potassium

level of the blood.

- Regulation has only one direction, and is not very

strong but still sufficient as passive regulation helps

out and potassium intake with food is relatively

constant in the long term. Potassium does not even

have a specific taste as sodium ion determines

primarily the salty taste.

Mechanism of action of aldosterone

Aldosterone

increases the

activity of the

Na-K pump

thereby

increasing

intracellular

potassium ion

level, which

leads to its

secretion to

the lumen of

the collecting

tube.

1. Hypothalamus 2. Pituitary 3. Epiphysis (pineal gland) 4. Thyroid (and parathyroid gland) 5. Thymus 6. Adrenal gland 7. Langergans’ islands of pancreas 8. Sex glands (ovary or testis)

Endocrine glands

Mineralocorticoids

Glucocorticoids

Sexual steroids

Catecholamines

Adrenal gland

Synthesis and regulation of aldosterone secretion

Outline of the lecture

1. Internal environment of living organisms,

homeostasis

2. Homeostatic regulations – endocrine system,

hormones

3. Examples of homeostatic regulations not

requiring the nervous system

– Potassium level of blood plasma

– Calcium level of blood plasma

4. Homeostatic regulations – nervous system

– Elements of the nervous system

– Hypothalamus

5. Examples of regulations involving the brain

– Water balance

Calcium content of human

Intracellular Ca

0.9%

Interstitial Ca

0.075%

Plasma Ca

0.025%

Total body calcium = 1500 g

Bone 99%

Bound to proteins– 45%

In complexes– 10%

Ionized free Ca – 45% Biologically active

fraction

Plasma Ca:

Calcium homeostasis

Extracellular

calcium (1500 mg)

Daily Ca intake

1000 mg

800 mg

200 mg

400 mg

200 mg

9.800 mg 10.000 mg

200 mg

200 mg

1. Hypothalamus 2. Pituitary 3. Epiphysis (pineal gland) 4. Thyroid (and parathyroid gland) 5. Thymus 6. Adrenal gland 7. Langergans’ islands of pancreas 8. Sex glands (ovary or testis)

Endocrine glands

Regulatory hormones of calcium homeostasis

Intracellular signaling of calcium receptor

PTH secretion is inhibited Calcitonon secretion is stimulated

Calcium receptor senses calcium ion level in the plasma

The major regulatory hormone is parathyroid hormone (PTH), which

increases calcium ion level in the plasma. PTH is produced in the

parathyroid gland when blood calcium ion levels decrease.

Another hormone, calcitonin has the opposite effects, it increases plasma

calcium ion level. Calcitonin is produced in C cells of the thyroid

hormone.

Target tissues of hormones regulating

plasma calcium ion level

• kidney

– Stimulates calcium ion reabsorption

– Stimulates the synthesis of vitamin D

• bone

– Stimulates osteolysis

• Gastrointestinal system

– No direct effect

– Vitamin D increases the absorption of calcium iom in the small intestine

Calcitonin:

Parathyroid hormone:

• bone

– Inactivates osteoclasts thereby inhibits osteolysis

Regulation of calcium homeostasis

extracellular

calcium (1500mg)

Daily Ca intake

1000 mg

800 mg

200 mg

400 mg

200 mg

9.800 mg 10.000 mg

200 mg

200 mg

PTH Vitamin D

Calcitonin

Comparison of the regulation of plasma

calcium to that of potassium ion

• Parathyroid hormone increases calium ion level while aldosterone descreases potassium ion level, so the major direction of regulation is the opposite

• Calcium ion level can be regulated in both direction as not only parathyroid hormone but also calcitonin plays a role, which has opposite effect on plasma calcium level

• Parathyroid hormone acts to increase calcium ion levels in 3 different tissues while aldosterone regulates potassium ion level only in the kidney

• Parathyroid hormone has indirect effects, too. It includes another hormone, vitamin D in the control of plasma Ca ion level

• Both regulation is coupled (potassium to sodium, calcium to phosphate), both opposing directions

• Neither regulations involves the nervous system