Bio Endo Neuro disorders

Peptides and Proteins

Water soluble, made from large precursor molecules prohormones.

What is the first step of transcription of peptide hormone?

Initiation (has a promoter and a starter gene for the synthesis of RNA polymerase II copies) 

What is the second step of transcription of peptide hormone?

Elongation (nucleotides are added to the 3' end of the chain and becoming displaced)

What is the third step of transcription of peptide hormone?

Termination (no more bases are added on and polymerase ends)

What are the three types of membrane receptors 

1. Ion channel linked receptors 

2. G-protein-linked receptors

3. Tyrosine kinase receptors

What are the four components of protein/peptide Hormone Signal Transduction 

1. Receptor on the cell surface

2. Intracellular mechanisms

3. Secondary messengers

4. Signaling pathways interactions

What are the five steps of ER goglgi network

1. Synthesis of ribosomes in the RER

2. Transport via the ER transporting vesicles to the golgi 

3. Packaging into secretory vesicles within the golgi transport to the plasma membrane

4. Plasma membrane fusion and opening to the cell surface

5.  Exocytosis to the extracellular space, organ duct or lumen

Pancreas

elongated, tapered organ located across the back of the abdomen, behind the stomach.

Exocrine tissue

pancreatic tissue that secretes digestive enzymes.These enzymes are secreted into a network of ducts that join the main pancreatic duct, which runs the length of the pancreas.

Endocrine tissue

The other main pancreatic tissue that is used for which consists of the islets of Langerhans, secretes hormones into the bloodstream.

What are the four major cell types that are found in the islets of langerhans

αlpha cells, Beta cells, Delta cells and F(pp) Cells

Alpha cells

produce glucagon. Glucagon is a hormone, mobilizing glucose, fatty acids and amino acids from stores into the bloodstream; tends to increase plasma glucose by stimulating hepatic glycogenolysis and gluconeogenesis; increases lipolysis in adipose tissue.

Beta cells

produce insulin. Insulin is a hormone, increasing the storage of glucose, fatty acids and amino acids.

Delta cells

produce somatostatin, which inhibits secretion of insulin, glucagon and pancreatic polypeptides.

F(or pp) Cells

responsible for the production of pancreatic polypeptides, which slows absorption of food.

Insulin biosynthesis

originally produced as preproinsulin, which is transformed into a prohormone molecule by proteolytic action intoproinsulin, and finally into the active polypeptide hormone,

Insulin

An anabolic hormone necessary for the uptake of glucose and amino acids by peripheral tissues especially skeletal muscle, cardiac muscle and adipose tissue. It is also involved in glycogen formation in liver and skeletal muscles, glucose conversion/ protein synthesis

Glucose

most important stimulus for insulin synthesis and release.

Glucose homeostasis

1. Glucose production in the liver

2. Glucose uptake and utilization by peripheral tissues (chiefly skeletal muscle)

3. The actions of insulin and counter-regulatory hormone glucagon.

Glycogenesis

Glucose to glycogen

Glycogenolysis

Glycogen to glucose

Gluconeogenesis

Amino acids to glucose

Lipogenesis

Glucose or free fatty acids (FFA) to fats

Lipolysis

Fats to FFAs & Glycerol

Adipose tissue

Increased Glucose uptake & Lipogenesis

Decreased Lipolysis

Striated muscle

Increased Glucose uptake, Glycogen & protein synthesis

Liver

Decreased Gluconeogenesis Increased Glycogen sythesis and lipogenesis

Diabetes mellitus

chronic disorder of carbohydrate, fat and protein metabolism with long term complications affecting blood vessels, kidneys, eyes and nerves.

Diagnosis of Diabetes

Blood glucose is elevated beyond 70-120 mg

1. Random glucose >250 mg/dl and appropriate symptoms.

2. Fasting glucose level > 126mg/dl

3. Abnormal glucose tolerance test, >200mg/dl 2 hours after

ingestion of a standard carbohydrate load

Type I diabetes

an absolute deficiency of insulin secretion caused by pancreatic β-cell destruction. Also termed insulin dependent diabetes mellitus (IDDM)

Type II diabetes

combination of peripheral resistance to insulin action and an inadequate compensatory response of insulin secretion by pancreatic β-cells. This is termed non-insulin dependent diabetes mellitus (NIDDM)

What are the two main defects of type II diabetes

[1] β-cell dysfunction and insulin resistance

[2] relationship between body fat and insulin resistance

Insulin resistance

decreased ability of peripheral tissues to respond to insulin,

Environmental factors

Obesity is by far the factor most associated with the development of Type 2DM, the risk of diabetes increase directly with BMI. person with a BMI of 18.5 to 24.9 is considered to be at a healthy

β-cell Dysfunction

inadequate insulin secretion in the face of insulin resistance and hyperglycemia.

β-cell dysfunction - qualitative:

Decreased normal pulsatile insulin secretion in response to hyperglycemia and temporal variation is secretion.

β-cell dysfunction quantitative

defects associated with decreased β-cell mass.

Compensatory B-cell hyperplasia

Leads to normoglycemia

Pathogenesis factors of Type I DM

Linkage to MHC Class II HLA genes. Autoimmune destruction of B-cells mediated by T-cells and humoral mediators.

Pathogenesis factors of Type II DM

No HLA Linkage to candidate diabetogenic genes. Insulin resistance in skeletal muscle, adipose tissue and liver β-cell dysfunction and relative insulin deficiency

Monogenic forms of Diabetes

These are uncommon causes of Diabetes but given the number of

diabetics these are not small populations.

Mechanism of Islet B-cells destruction

T-cells react against β-cell antigens resulting in cell damage. T-helpers activate macrophages directed at β-cell.Cytotoxic T-cells directly kill β-cells.

What are the symptoms of low blood sugar?

Sweating, Dizziness, Anxiety, Blurred vision, Restlessness

Metformin

It is drug used to lower blood glucose

Metformin on the liver

Lowers lipid synthesis and gluconeogenesis

Metformin on the adipose tissue

Decrease fatty acid synthesis and lipolysis

Metformin on the muscle

Increased mitochondrial oxidation, fatty acid & glucose uptake, and glycolysis

Metformin on the pancreas

Insulin secretion

Glucagon signaling (Downstream)

Starts in serpentine protein, Then moves to Adenylate cyclase, moves to Cyclic AMP, To PKA, Lastly ChREBP

Glucagon Signaling (Upstream)

GCPR protein, Adenylate cyclase, Cyclic AMP, PKA, Fru-2,6-P2

Glucagon on the liver

Stimulates glycogenolysis, Gluconeogenesis, Lipolysis and ketogenesis

Inhibits glycolysis

Diabetic Neuropathy

Peripheral neuropathy affecting both motor and sensory nerves due to myelin degeneration and axonal damage.

Diabetic microvascular disease

affects the retina, kidneys and peripheral nerves resulting in diabetic retinopathy, nephropathy and neuropathy.

Diabetic macrovascular disease

Accelerated atherosclerotic disease of the aorta, large and medium sized arteries - result in increased risk of myocardial infraction, stroke, aortic aneurysms and Peripheral Vascular Disease (PVD).

Two particular metabolic disorders

Diabetic ketoacidosis/ Nonketotic hyperosmolar coma

Nonketotic hyperosmolar coma

due to hyperglycemia and dehydration due to an osmotic diuresis. More common in type II DM

Diabetic ketoacidosis

severe insulin deficiency and increased glucagon levels; excessive release of fatty acids with hepatic oxidation generates ketone bodies. Primarily exclusive to Type I DM

What is the three concentric rings in the cortex

Zona Glomerulosa, fasiculata, reticularis

Secretory function of the Zona glomerulosa

Mineralocorticoids(Aldosterone)

Secretory function of the Zona fasiculata

Glucocorticoids (Cortisol) (Corticosteroids)

Secretory function of the Zona reticularis

Sex steroids

Hormone secretion of Zona Glomerulosa

Aldosterone (primarily) Mineralocorticoid, Na+/K+/H2O+ balance

Biosynthesis of aldosterone

Cholesterol>Pregnolone>Progesterone>11-Deoxycortisterone>Cortisterone>Aldosterone

Two key steroid enzyme for aldosterone and cortisol

11-Beta-hydroxylase, 21-Hydroxylase

Cortisol Biosynthesis pathways

Cholesterol>Pregnenolone>Progesterone or 17-Alpha-Hydroxypregnolone> 17-alpha-Hydroxyprogesterone>11-dexycortisol>cortisol

Control renin-Angiotensin system

Angiotensinogen(renin, Kidney)>Angiotensin I(Angiotensin converting enzyme lungs)>Angiotensin II.

Hormone secretion in the Zona fasiculta

Glucocorticoids (Steroid hormone) Cortisol(mainly) Corticosterone, cortisone

Hormone action of the Zona Fasiculta

Increase metabolic availability of glucose and fatty

acids

• Depress immune response

• Depress inflammatory response

What are the four different types of steroids produced from the cortex

Cortisol>Corticosterone>aldosterone>4-androstene

Common disease of the adrenal cortex

 Congenital Adrenal Hyperplasia

 Addison’s Disease

 Cushing’s Syndrome

CONGENITAL ADRENAL HYPERPLASIA

 Autosomal recessive disorder in

21 Hydroxylase 11β Hydroxylase deficiency

 Other enzyme deficiencies are extremely rare

Cushing’s Syndrome

syndrome due to excess cortisol from pituitary, adrenal or other sources (exogenous glucocorticoids,ectopic ACTH, etc.)

Cushing’s disease

hypercortisolism due to excess pituitary secretion of ACTH (about 70% of cases of endogenous Cushing’s syndrome)

Cushing’s disease/Syndrome during pregnancy

Buffalo Hump, Moon Facies, Weight gain, Truncal obesity, proximal muscle wasting.

Synthesis of Epinephrine

Tyrosine> Dopa(via Tyrosine hydroxylate)>Dopamine(Via aromatic amino acid decarboxylase)>Norepinephrine(via Dopamine Beta hydroxylase)>Epinephrine

Prostaglandins function on the digestive system:

Gastric protection, Intestinal fluid secretion, Peptic ulcer

Prostaglandins function on the respiratory system:

Airway resistance and Asthma

Prostaglandins function on the nervous system:

Sleeping and Fever

Prostaglandins function on the immune system:

Modulation of inflammatory cells

Prostaglandins function on the excretory system:

Maintenance of salt- water balance

Prostaglandins function on the cardiovascular system:

Maintenance of blood pressure and Platelet aggregation

Prostaglandins function on the Musculoskeletal system:

Contraction and Relaxation of smooth and skeletal muscles, and bone formation

Ulf von Euler

Founder of the prostaglandin in 1936

Prostaglandin biosynthesis

Phospholipids>Arachidonic acid>PGG2>PGH2

What does PGH2 produced

PGI PGD PGE PGF2a TxA

All receptors Increase Cyclic AMP except

EP3a, EP3d(Increase IP3), and constrictor receptors

Cellular transport of prostaglandins

PGs predominate as charged anions and diffuse poorly through plasma membranes despite of their lipid nature. carrier-mediated transport mechanism is inevitable for

the transport of PGs\

PGE2 Signaling-1

PGE2 connects to a receptor (Either EP1,EP3a,d or EP2 EP3b,C or EP4) then goes through the GQ or GS protein pathways. SRC(protein kinase) connects the two together to Phosphoralate to secondary messengers for specific genes

PGE2 Signaling-2

PGE2 connects to a GPCR protein. Then GRK is connected to the serpentine receptor and phosphorylated. Then B-arr along with SRC switches out GRK. Finally connecting with EGFR>PI-3k> AKT> increased migration and metastasis

Map Kinase (ERK1/2)signaling pathway

Ras>C-Raf>Mek1/2

Steroid Hormones

Derives from cholesterol and differ only in the ring structure and side chains attached to it. Are not packaged, but synthesized and immediately released

Different types of steroid hormones

Glucocorticoids, Mineralocorticoids, Androgens, Estrogens, and Progestogens

Steroid Hormone Biosynthesis

Derived from cholesterol. A series of enzymatic steps in the mitochondria and ER of steroidogenic tissues convert cholesterol into all of the other steroid hormones and intermediates.Lastly using a rate limiting step via a process called steroidogenic acute regulatory protein (STAR)

Progesterone biosynthesis

Cholesterol>(P450 SCC) Pregnenolone> (3BH5D(3)) Progesterone

Estradiol Biosynthesis

Cholesterol>Pregnolnone>Progesterone>17-Hydroxyprogesterone>Androstenedione> Testosterone or estrone> Estradiol

Mechanism of activation of steroid hormones

Steroid is secreted

. Passes into cell

. Into nucleus

. Binds receptor, DNA

. Activates or represses

transcription

. Controls translation

. Peptide alters cellular activity

Steroid hormone receptors

Named nuclear receptors and function as ligand activated transcription factors.

Steroid hormone receptors purpose

Bind to DNA as homodimers and recognize a palindromic response elements

Structure of NRs

Beginning in the N-Terminus where A/B domain has transactivation activity

NR’s bid to hormone via elements(HRE’s) in their target DNA binding domain(C domain)

D(Hinge) domain

Ligand binding domain or E/F domain varies on which NRs