*Transmembrane receptor are proteins that span the thickness of the plasma membrane of the cell, with one end of the receptor outside (extracellular domain) and one inside (intracellular domain) the cell.

*Nuclear (or cytoplasmic) receptors are soluble proteins localized within the cytoplasm or the nucleoplasm. The hormone has to pass through the plasma membrane, usually by passive diffusion, to reach the receptor and initiate the signal cascade.

Gi - ion channels, inhibiton of cAMP, phospholipases

Gs - increase cAMP

Gq - increase DAG and IP3

G12,13 - activates Rho

-ligand binding changes the confirmation of the receptor so that specific ions flow through it

-the resultant ion movement alters the electric potential across the plasma membrane

-found in high numbers on neuronal plasma membranes e.g. ligand-gated channels for sodium and potassium

-also found on the plasma membrane of muscle cells

-lack intrinsic catalytic activity

-binding of the ligand results in the formation of a receptor dimer (2 receptors)

-this dimer than activates a class of protein called tyrosine kinases

-this activation results in the phosphorylation of downstream targets by these tyrosine kinases (stick phosphate groups onto tyrosines withinthe target protein)

-receptors for certain cytokines and interferons

also called receptor tyrosine kinases OR ligand-triggered protein kinases

-similar to tyrosine-linked receptors

- ligand binding results in formation of a dimer -BUT: they differ from tyrosine-linked receptors - intrinsic catalytic activity

*means that ligand binding activates it and the activated receptor acts as a kinase

*recognize soluble or membrane bound peptide/protein hormones that act as growth factors - e.g. NGF, PDGF, insulin

-binding of the ligand stimulates the receptor’s tyrosine kinase activity,

-results in phosphorylation of multiple amino acid residues within its target such as serine and threonine residues

-this phosphorylation activates downstream targets

*its targets are generally other protein kinases which phosphorylate their own downstream targets

*Hormone stimulation of Gs protein-coupled receptors leads to activation of adenylyl cyclase and synthesis of the second messenger cAMP

*cAMP does not function in signal pathways initiated by RTKs

*cAMP and other second messengers activate specific protein kinases (cAMP-dependent protein kinases or PKAs)

*cAMP has a wide variety of effects depending on the cell type and the downstream PKAs and other kinases

*second messenger systems allow for amplification of an extracellular signal

IP3 and DAG are breakdown products of phosphotidylinositol (PI)

*produced upon activation of multiple hormone receptor types (GPCRs and RTKs)

*best characterized signal transduction pathway activation of RTKs by growth factors, hormones etc

*result in activation of an adaptor protein called Ras GTPase

*ras induces a kinase signal cascade that starts with a kinase called rac and culminates in activation of a MAP kinase (MAPK)

*in between are a series of kinases that are part of the cascade

*MAPK activation results in translocation into the nucleus and phosphorylate many different proteins, including transcription factors that regulate gene expression

ERK 1 and 2 - growth, differentiation, development

p38 MAPK, SAPK, JNK 1, 2, and 3 - inflammation, apoptosis, growth, differentiation

1) ligand binds to receptor and receptor dimerizes

2) autophosphorylation of tyrosines

3) binding of cystolic proteins with SH2 domains

4) activated PLC stimulates IP3 and DAG pathway

5) activated GRB2-Sos stimulates Ras pathway

*Overexpression and gain of function mutations in receptor and nonreceptor tyrosine kinases in cancer (e.g. EGF receptor and HER2, Src family kinases, and Bcr-Abl), and skeletal malformation (FGF receptors)

*Loss of function mutations in receptor (e.g. insulin receptor in diabetes and Ret/GDNFR in Hirschsprungs disease) and nonreceptor tyrosine kinases (e.g. ZAP70 and Jak3 in SCID, and Btk in hereditary agammaglobulinemia)

*Overexpression of tyrosine phosphatases in cancer (e.g. PRL-3 in metastatic colon carcinoma)

*Loss of function mutations in tyrosine/lipid phosphatases (e.g. CD45 in SCID, PTEN and MKP1 in cancer, and MTMR1 in peripheral neuropathy)

*Specific rates and rhythms of secretion -Diurnal, pulsatile and cyclic, and patterns depending on circulating substances

*Operate within feedback systems

*Affect only cells with appropriate receptors

*The liver inactivates hormones, rendering the hormones more water soluble for renal excretion

*pituitary gland

*thyroid gland

*parathyroid glands

*adrenal medulla

*ovary or testis

*Hormones are released:

-In response to an alteration in the cellular environment

-To maintain a regulated level of certain substances or other hormones

*Hormones are regulated by chemical, hormonal, or neural factors

-Negative feedback

-Positive feedback

Hormones are released into the circulatory system by endocrine glands

*Water-soluble hormones circulate in free, unbound forms

*Lipid soluble hormones are primarily circulating bound to a carrier

Protein hormones - binds to plasma membrane receptors; its effects are the most rapid of all the hormone classes

i. Oxytocin

ii. Adrenocorticotrophin

Amine hormones - bind to plasma membrane receptors and has the same relatively fast receptor response as protein hormones

i. Epinepherine

ii. Norepinepherine

iii. Melatonin

Steroid & Other Small Hormones - binds to the intercellular receptors; slow mechanism of action compared to protein hormones

i. Gonadal hormones: estrogen, progesterone, androgens

ii. Adrenal hormones: glucocorticoids, mineralocorticoids

iii. Thyroid hormones

Derivatives of Tyrosine

*Catecholamines - EPI, NE

*Thyroid hormones - T3 and T4

Derivative of Tryptophan - Melatonin

Peptide Hormones

*Glycoproteins - EPO (kidney), TSH,LH,FSH (pituitary gland)

*Short polypeptides - insulin, glucagon (pancreas), parathyroid hormone

Lipid Derivatives

*Eicosanoids - leukotrienes, prostaglandins, etc

*steroid hormones - androgens, estrogens

α2 -Adrenergic catecholamines

ß-Adrenergic catecholamines

Adrenocorticotropic hormone

Antidiuretic hormone

Calcitonin

Follicle-stimulating hormone

Glucagon

Lipotropin

Luteinizing hormone

Melanocyte-stimulating hormone

Parathyroid hormone

Somatostrain

Thyroid-stimulating hormone

*Atrial natriuretic factor

*Nitric oxide

*Acetylcholine (muscarinic)

*α1- Adrenergic catecholamines

*Angiotensin II

*Antidiuretic hormone (vasopressin)

Cholecystokinin

Gastrin

*Gonadotropin

*Oxytocin

Adiponectin

Chorionic

somatomammotropin

Epidermal growth factor

*Erythropoietin

Fibroblast growth factor

Growth hormone

*Insulin

*Insulin-like growth factors I and II

Leptin

Nerve growth factor

Platelet-derived growth factor

Prolactin

Extracts iodine ("the fuel") from the bloodstream

Produce two thyroid hormones called:

Thyroxine (T4) - tetraidodothyronine Triiodothyronine (T3) - triiodothyronine

Secretes thyroid hormone

In its target tissues, tyroxine (T4) is converted to either the more active triiodothyronine (T3) or to inactive reverse T3

Affect every cell, tissue and organ in the human body

Thyroid gland

Two lobes lateral to the trachea

Isthmus

Follicles (follicle cells surrounding colloid)

Parafollicular cells (C cells) -Secrete calcitonin

Regulation of thyroid hormone secretion -Thyrotropin-releasing hormone and thyroid stimulating hormone

90% T4 and 10% T3

Bound to thyroxine-binding globulin, thyroxine-binding prealbumin, or albumin

Affect growth and maturation of tissues, cell metabolism, heat production, and oxygen consumption

Parathyroid glands

*Small glands located behind the upper and lower poles of the thyroid gland

*Produce parathyroid hormone

-Regulator of serum calcium

-Antagonist of calcitonin

1. Too little thyroxin - hypothyroidism

a. Depression (clinical or subclinical), attention & memory problems

2. Too much thyroxin - hyperthyroidism

a. Agitation, irritability, & weight loss

*Goiters - Growths on thyroid gland

PTH, a peptide

*Raises blood calcium levels.

*Secretion regulated by calcium in the blood.

*Causes osteoclasts to break down bone, releasing Ca2+ into the blood.

Stimulates the kidneys to reabsorb Ca2+.

Stimulates kidneys to convert vitamin D to its active form.

PTH and calcitonin (from the thyroid gland) are antagonistic hormones.

Rise in Ca2+ level will inhibit PTH (negative feedback)

Decrease in Ca2+ level will inhibit calcitonin (negative feedback)

A lack of PTH causes hypoparathyoidism, a tetany. Calcium levels in the blood drop. There are convulsive contractions of the skeletal muscles

The pancreas is both an endocrine and an exocrine gland

Houses the islets of Langerhans

Secretion of glucagon and insulin Cells

*Alpha release glucagon

*Beta release insulin

*Delta release somatostatin and gastrin

*F cells release pancreatic polypeptide

Insulin is synthesized as a preprohormone a single polypeptide with 103 amino acids in the beta cells of the islets of Langerhans.

In ER by the action as signal peptidase, gives proinsulin.

Then secretory vesicles in golgi enzymes cleaved a paired amino acid residues and formation of equimolar amounts of mature insulin and C peptide. (C= connecting).

Insulin and C-peptide is released together into the blood

*Secretion is promoted by decreased blood glucose levels

*Stimulates glycogenolysis, gluconeogenesis, and lipolysis

*Renin converts angiotensinogen to angiotensin I

*ACE converts angiotensin I to angiotensin II

*Angiotensin II causes vasoconstriction which elevates blood pressure

*Angiotensin II also causes release of aldosterone from the adrenal system

*Aldosterone increases Na/H20 retention which elevates blood pressure