Topics to Review Homeostasis Cell membrane structure Cell membrane proteins Synthesis and Exocytosis of secreted proteins Transcription and Translation Transmembrane transport Membrane potential

Cellular Communication The body’s 100 trillion cells need to communicate in a manner that is rapid and conveys a tremendous amount of information and occurs by 2 types of physiological signals Chemicals –molecules that are secreted from cells into the extracellular fluid The cells that receive the chemical or electrical signal are called target cells Electrical –changes in the membrane potential of a cell

Methods of Cellular Communication Gap junctions –direct cytoplasmic transport of electrical (ions) and or chemical signals between adjacent cells Contact-dependent signals –cell surface molecules on the cell membrane of one cell attach to cell surface molecules on the cell membrane of an adjacent cell Local communication –chemical signals that are released into the extracellular fluid from one cell diffuses a short distance to regulate itself and or a neighboring cell (autocrine and paracrine)

Long distance communication -chemical signals (hormones) transported via the circulatory system (endocrine and neuroendocrine) –electrical signals (action potentials) carried along axons of nerve cells (nervous) which result in the secretion of neurotransmitters

Hormones are secreted from: –the glands of the endocrine system see figure –some organs heart, kidneys, stomach, skin, liver, ovaries and testes

Control of Hormone Secretion (Release) The hypersecretion or hyposecretion of a hormone from a gland leads to too high or inadequate levels of circulating hormone leading to pathological conditions Following a particular stimulus, the gland can increase or decrease the rate of secretion Circulating (blood) levels of hormones are not permitted to get too high because they are controlled by 2 separate negative feedback loops -activity of the target returns variable to the set point –circulating hormones decrease further secretion from the gland of origin

endocrine cells have protein receptors to the hormones that they secrete and hormone secretion is decreased when these receptors are bound by a hormone (autocrine)

Endocrine Gland or Organ Target Cell Stimulus hormone Changes its activity hormone secretion inhibits additional secretion variable returns to set point inhibits additional secretion

Stimuli that Alter Hormone Secretion Hormone secretion rates from glands can be altered in response to: –humeral stimuli changes in levels of substances in blood –glucose, K +, CO 2, pH… –neural stimuli neurotransmitters exocytosed onto a gland by a neuron –hormonal stimuli hormones secreted from one gland or organ will stimulate another gland or organ to secrete a hormone

Neurotransmitter vs Hormonal Control The responses to neurotransmitters are: –very rapid action potentials travel at speeds up to 270 mph response occurs within sec. after secretion –very short lived (simple reflex) neurotransmitters are either rapidly hydrolyzed in the synaptic cleft or are endocytosed out of the synaptic cleft back into the neuron The responses to hormones are: –slow distribution by blood can take seconds to minutes Responses at target can take minutes to hours before it can be measured

–long lasting hormones can stay in the blood for minutes to days continuously causing an effect on the target

Nervous System vs Endocrine System Reflexes

Signaling Chemicals The amount signaling chemicals that are released from cells reflects the amount of response required to maintain homeostasis –The amount of chemical messenger released is directly proportional to the extent of a homeostatic imbalance The magnitude of the response of a target cell to a signaling chemical depends largely on the amount of chemical messenger that is at the target cell –The greater the amount of chemical messenger at the target cell, the greater the response

Signal Molecules Signaling chemicals that are released by cells are considered to be the first messengers because they are responsible for initiating a series of events that ultimately lead to a response 2 distinct groups based on their chemistry and how they behave when they reach their target cells –Hydrophobic (non-polar) chemicals diffuse through the cell membrane and enter the cytoplasm of the target cell steroid hormones –synthesized from cholesterol –names end in the suffix “-one” or “-ol” –Hydrophilic (polar) chemicals are unable to cross the cell membrane of the target cell and therefore affect the cell from its surface

peptide hormones (3 to over 200 amino acids) monoamines (amino acid derivatives)

Hormone Synthesis: Steroid Hormones synthesized from cholesterol in SER and diffuses out of the cell differ in functional groups attached to 4-ringed steroid backbone

Hormone Synthesis: Peptides synthesized in RER as a prohormone Golgi complex further modifies it into hormone secreted out of cell by exocytosis

Receptor Proteins In order for a chemical signal that is secreted from a cell into the extracellular fluid to create a response in a target cell, the target cell must possess a receptor protein to which the signal chemical binds Receptor proteins are either located: – on the surface of the cell membrane for hydrophilic signaling chemicals –in the cell for hydrophobic signaling chemicals A single cell may have between 500 and 100,000 receptor proteins which allow it to respond to a variety of signaling chemicals If a cell does not have a receptor protein that recognizes a particular signaling chemical, the cell will have no response

Down-Regulation of Receptor Proteins -If the signaling chemical concentration is abnormally high for a sustained period of time creating too large of a response, the target cell can bring the response back to normal by a reduction of the receptors Down-regulation is partially responsible for drug tolerance, where the response of a given dose decreases despite constant exposure –increasing doses are therefore required to elicit a constant response

Up-Regulation of Receptor Proteins Up-regulation of protein receptors is the opposite whereby a decrease in the concentration of signaling chemical causes the target cell to increase the number of protein receptors to normalize the response

Hormone Transport in Blood Peptides and monoamines mix easily with blood Steroid hormones must bind to hormone binding proteins in the blood –the binding of a steroid hormone to the binding protein is reversible -bound hormones are attached to a binding protein and are moved through the circulatory system once unbound, the hormone exits the circulatory system to affect the target cell

Hormone Transport and Action on Target

-Both classes of chemicals will change the activity of a target cell by changing the activity of proteins in a cell (recall proteins perform EVERY cellular function) –some proteins will be activated, some will be inactivated and some will be unaffected the response of a target cell is very specific Hydrophobic signaling molecules alter protein synthesis to increase or decrease the number of proteins in a target cell (slow response) Hydrophilic signaling molecules change the activity of proteins that are currently in a target cell (fast response) –“flipping” a molecular switch ON or OFF

Hydrophobic Signal Molecules Following the diffusion of these chemicals into the cytoplasm of a target cell they bind to a receptor protein located either in the cytoplasm or in the nucleus The binding of the signaling chemical to the protein receptor initiates changes in the rate of transcription of genes in the target cell This ultimately changes the number of proteins in the target cell thus altering its activity

Mechanism of Steroid Hormone Action

Hydrophilic Signal Molecules Since these chemicals are unable to pass through the cell membrane, the receptor proteins for these molecules are integral (transmembrane) proteins with 3 distinct regions –an extracellular portion that binds to the signaling chemical –an intracellular portion that instructs the target cell how to respond to the signaling chemical -a membrane spanning portion that “connects” the extracellular portion to the intracellular portion

Hydrophilic Signal Molecules Following the binding of the signaling chemical to the protein receptor, one of 2 events occur –if the protein receptor is a channel, the signaling chemical either opens or closes it which alters the membrane potential of the target cell –if the protein receptor is not a channel, information is transferred through the cell membrane of the target cell and then transformed into an intracellular response this process is referred to as signal transduction –a transducer is a device that converts a signal from one form into another

Signal Transduction A biological transducer converts the message of an extracellular signaling chemical into intracellular messages which triggers a response in a cell In biological systems the signal is not only transformed, but it is also amplified (made larger) -These pathways rely on cell membrane receptor proteins and the production of intracellular second messenger molecules that translate the signal from the first messenger (eg. hormone) into cellular responses

Signal Cascades When a signaling chemical binds to the membrane protein receptor, the receptor initiates a series of responses beginning at the receptor and moving into the cell The sequence of reactions begins with the conversion of an inactive molecule (A) into an active form Activated A converts an inactive molecule (B) into active B which converts inactive C into active C and so on until at the final step, an intracellular substrate is converted into a product

G Proteins GTP binding proteins, located on the cytoplasmic face of the membrane, link membrane protein receptors either to ion channels or to membrane enzymes The binding of a signaling molecule to a membrane protein receptor activates a G protein which will either: –open an ion channel in the membrane –stimulate or inhibit an amplifier enzyme

Adenylyl cyclase and cyclic AMP (cAMP)

Phospholipase C and IP 3 and DAG and Ca 2+

Amplifier Enzymes and Second Messengers -Amplification enzymes synthesize second messenger molecules during the process of signal transduction Second messengers are intracellular molecules that provide a means to influence the internal functioning of a cell by signaling chemicals (hormones) that cannot enter the cell 2 key enzymes that synthesize 2 nd messengers –adenylyl cyclase catalyzes the conversion of ATP into the second messenger cyclic AMP (cAMP) –phospholipase C catalyzes the conversion of a membrane phospholipid into 2 different 2 nd messengers Diacylglycerol (DAG) Inositol triphosphate (IP 3 ) –in some signal cascades IP 3 stimulates the release of calcium ions from the smooth ER into the cytoplasm acting as a third messenger

Protein Kinases -Second messenger molecules activate protein kinases which transfer a phosphate group (PO 3 - ) from ATP to a protein in a process called phosphorylation The phosphorylation of proteins sets off a series of intracellular events that lead to the ultimate cellular response (conversion of substrates into products) -This response is dependent on the type of protein kinase (over 100 different types discovered) that is activated and the proteins that is (are) phosphorylated –metabolic enzymes –transport proteins –proteins that regulate gene transcription

Hypothalamus and Pituitary The anatomically superior hypothalamus and the pituitary are located in the brain –the hypothalamus controls the secretion of hormones from the pituitary gland which in turn controls the secretion of hormones from other glands including the thyroid gland, adrenal glands and the gonads (ovaries/testes) -The hypothalamus is composed of neurons which secrete hormones into the bloodstream The pituitary gland is divided into two halves –Anterior (adenohypophysis) is composed of glandular (epithelial) tissue

–Posterior (neurohypophysis) is composed of collection of axons and axon termini whose cell bodies and dendrites are located in the hypothalamus

Hypothalamus and Pituitary (Hypophysis)

Hypothalamic Control of the Anterior Pituitary The hypothalamus secretes releasing hormones which travel through a portal circulation and stimulate the secretion of anterior pituitary hormones –Thyrotropic Releasing Hormone (TRH) secreted when body temperature decreases and stimulates the secretion of Thyroid stimulating hormone (TSH) which targets the thyroid gland –Corticotropic Releasing Hormone (CRH) secreted in times of stress and stimulates the secretion of Adrenocorticotropic hormone (ACTH) which targets the adrenal glands –Gonadotropic Releasing Hormone (GnRH) secreted when testosterone or estrogen levels are low and stimulates the secretion of Follicle stimulating hormone (FSH) & Luteinizing hormone (LH) which targets the testes or ovaries

Hypothalamus and Anterior Pituitary

Control of Releasing and Stimulating Hormones Hormones secreted from the thyroid gland, adrenal glands and gonads create a response in their respective targets These hormones also target the hypothalamus, anterior pituitary and the gland of origin to INHIBIT additional secretion of the releasing hormone, stimulating hormone This ensures that the amount of hormone that is secreted from each gland is just enough to create an appropriate change in the body –prevents hypersecretion

Other Hormones of the Anterior Pituitary Growth hormone (GH) –A peptide hormone that stimulates the liver to secrete a class of hormones called insulin like growth factors (IGFs) -IGFs targets skeletal muscle, bone and cartilage and stimulate protein synthesis (growth) IGFs also targets adipose tissue and stimulates lipolysis (fat breakdown) to encourage the body to use fats as an additional energy source for growth Prolactin –stimulates milk production by the breasts

Posterior Pituitary Secretes 2 neurohormones into circulation following stimulation of the hypothalamus: Antidiuretic hormone (ADH) or Vasopressin –secreted in response to: a decrease in body water content decrease in blood pressure an increase in extracellular solute concentration –targets the kidneys and causes a reduction in the volume of urine produced retains body H 2 O increases in blood pressure decreases extracellular solute concentration –Hyposecretion results in diabetes insipidus very high urine volume that contains no glucose

Oxytocin –stimulates the contraction of smooth muscle in the uterus and breasts during childbirth and nursing

Hypothalamic Control of the Posterior Pituitary

Thyroid Gland Largest pure endocrine gland Covers the anterior and lateral sides of trachea

Thyroid Gland The thyroid gland consists of thousands of follicles are spheres bordered by follicular cells (simple cuboidal epithelium) filled with colloid secrete the thyroid hormones Parafollicular (C) cells are found between follicles secrete the hormone calcitonin

Thyroid Hormones The thyroid hormones, T 4 (thyroxine) and T 3, are considered to be steroid-like hormones –are nonpolar –have intracellular receptors that influence gene transcription -Made from 2 nonpolar amino acids of tyrosine bound to either 4 or 3 atoms of iodine -Increase the metabolic rate by accelerating the rate of cell respiration which produces a significant amount of heat energy Recall that the secretion is controlled by the hypothalamic and anterior pituitary hormones in response to a decrease in body temperature (BT) –↓BT → TRH → TSH → thyroid hormone

Adrenal Glands The adrenal glands (toward kidney) are pyramid- shaped glands on top of each kidney are structurally and functionally two glands in one: –Adrenal cortex (outside) epithelial tissue organized in 3 layers (zona) –Zona glomerulosa (superficial layer) –Zona fasciculata (middle layer) –Zona reticularis (deep layer) –Adrenal medulla (center of gland) nervous tissue that is the hormonal branch of the sympathetic nervous system (fight/flight)

Adrenal Glands

Adrenal Cortex -Secretes hormones called corticosteroids -Different corticosteroids are produced in each zona –Zona glomerulosa mineralocorticoids (mainly aldosterone) –control body levels of sodium and potassium –Zona fasciculata glucocorticoids (mainly cortisol) –control blood levels of substrates for metabolism (glucose, fatty acids and amino acids) –Zona reticularis gonadocorticoids (mainly androgens (male sex steroid hormones)) –secreted at low levels in males and females and may attribute to the onset of puberty

Aldosterone (mineralocorticoid) Is secreted in response to any of the following stimuli: –an increase in blood K + levels –a decrease in blood Na + levels –a decrease in blood pressure –secretion of ACTH from the anterior pituitary The target of aldosterone is the kidney –The kidneys respond to aldosterone by: increasing K + urination (which decreases blood K + levels) decreasing Na + urination (which increases blood Na + levels) –an increase in Na + levels in the blood causes an increase in blood pressure

Cortisol (glucocorticoid) Is secreted in response to long term stress (lasting days/weeks/months) LTS → CRH → ACTH → cortisol Targets include: –Liver causing gluconeogenesis –the enzymatic synthesis of glucose from non- carbohydrate molecules such as amino acids which is subsequently released of into the blood to be used by cells for the purpose of ATP synthesis -Adipose causing lipolysis of triglycerides into free fatty acids which are subsequently released into the blood to be used by cells for the purpose of ATP synthesis

Adrenal Medulla A sympathetic condition (fight or flight) stimulates the sympathetic centers of the medulla oblongata which fires APs that propagate along sympathetic nerves that synapse with chromaffin cells (modified sympathetic neurons) of the adrenal medulla and secrete 2 catecholamines into circulation –epinephrine (epi) (adrenaline) –norepinephrine (norepi) (noradrenaline) Epinephrine and norepinephrine bind to adrenergic receptors on targets including: –Liver stimulating the enzymatic hydrolysis of glycogen (glycogenolysis) into glucose in the liver which is subsequently released into the blood

-Adipose stimulates lipolysis to ↑ blood fatty acids –Cardiovascular system which increases the heart rate, strength of the heart beat and blood pressure to send blood around the body more quickly

Pineal Gland -posterior of third ventricle -pinealocytes: synthesize melatonin from serotonin -secretion on diurnal cycle: high at night, low during daylight Melatonin functions: -play role in timing of sexual maturation - antioxidant (free radical protection) -sets circadian rhythms Heart -some cells of atrial walls secrete Atrial Natriuretic Peptides (ANP)in response to stretch -ANP promotes Na+ and water loss at kidney, inhibits release of renin, ADH, and aldosterone to reduce BP and volume

Thymus -located deep to sternum -cells produce thymosins -promote development and maturation of T lymphocytes and the immune response Gonads A.Testes (male) -Interstitial cells produce androgens in response to LH Testosterone (most common) -produces male secondary sex characteristics -promotes sperm production -maintains secretory glands

B. Ovaries (female) -Follicle cells produce estrogens in response to LH and FSH Estradiol (most important) -produce female secondary sex characteristics -support maturation of oocytes -stimulate growth of uterine lining -Surge in LH causes ovulation, follicle reorganizes to form corpus luteum :produces estrogens and progestins Progesterone (most important)-prepares uterus for embryo growth -accelerates movement of oocyte/embryo to uterus ( the hormone of pregnancy)- produced in ovaries -enlargement of mammary glands

Progesterone - causes maturation of breasts Prolactin - causes production of milk (hypothalmus). When Progesterone levels drop, suckling causes stimulation. High level of this hormone decreases Libido. Oxytocin –(pituitary) aides in milk being squeezed out of breasts (milk letdown). Stimultaes muscle cell in seconds of suckling. Emotional influences also increase Oxytocin. A crying Baby may stimulate milk letdown. Hormones affecting the breasts

Common Disorders of the endocrine system 1. Pituitary Gland a. Diseases of Growth Hormone: -Excess: (usually due to pituitary tumor) -before epiphyseal closure = gigantism-after = acromegaly: excessive growth of hands, feet, face, internal organs -Deficiency: pituitary dwarfism: failure to thrive 2. Thyroid Gland a.Hypothyroidism = lack of T3/T4 Myxedema (adults): lack of iodine, causes low body temp, muscle weakness, slow reflexes, cognitive dysfunction and goiter = swollen thyroid

Gigantism Excessive growth hormone before the growth plates fuse. –Good for basketball –Bad for horse racing.

Acromegaly To much GH usually after the growth plates have fused. –Results in great wrestlers.

Dwarfism Hyposecretion of GH May require GH replacement therapy

Cretinism (infants): genetic defect, causes lack of skeletal and nervous system development b. Hyperthyroidism = excessive T3/T4, causes high metabolic rate, high heart rate, restlessness, fatigue c. Graves Disease = autoimmune disorder, produce antibodies that mimic TSH causing overproduction of thyroid hormones 3. Adrenal Gland a. Cushing’ s Syndrome = excessive corticosteriods (increase ACTH from pituitary tumor), results in: hyperglycemia, decrease muscle and bone mass, hypertension,edema, poor healing, chronic infections b. Addison’s Disease= deficient in corticosteriods, results in: weight loss, hypoglycemia, decrease Na+ increase K+ in plasma,dehydration, hypotension

Endemic goiter Goiter = enlarged thyroid gland –results from dietary iodine deficiency. –Can’t produce TH, –no feedback to Pituitary  TSH –This causes hypertrophy of the thyroid gland.

Toxic goiter (Graves disease) Antibodies mimic TSH causing  ’d TH to be released, Excessive Thyroxin levels –elevated metabolism – heart rate –weight loss –nervousness –exophthalmos (bulging eyes) –ANS induced sweating.

Cushing Disease

Addison's Disease Results from a hyposecretion of ACTH or an autoimmune disease that damages the adrenals. Results in decreased glucocorticoids and mineralocorticoid release. Results in hypotension and hypoglycemia Corticosteroid replacement therapy

4. Pancreas a. Diabetes mellitus = too much glucose in blood (hyperglycemia) Type I = failure to produce insulin Type II = insulin resistance, sometimes insulin deficiency Cells do not utilize glucose, ketone bodies produced, too many = ketoacidosis 5. Age Related Changes -very little change in most hormone levels -adverse effects due to changes in target tissues: prevent reception or response to hormone -gonads decrease in size and hormone production