CNS Homeostatic Mechanisms: Nervous and Endocrine Systems

Homeostatic Mechanisms

• Nervous and endocrine (hormonal) systems control body functions.
• The nervous system's effector response is fast, short, and targeted.
• The nervous system mainly regulates muscle activity, sensation, cognition or excretion.
• Neurotransmitters facilitate communication with target cells in the nervous system.
• The endocrine system's effector response is slower, long-lasting, and diffused compared to the nervous system.
• The endocrine system regulates metabolic functions, membrane transport, secretion, reproduction, growth, development and behavior.
• The endocrine system consists of glands without external ducts and specialized cells in areas like the GIT, CNS, and kidney that secrete hormones directly into the blood.

Endocrine Signaling

• An endocrine cell releases chemical signals (hormones), which are first messengers.
• Hormones diffuse into the blood/ECF and are transported to target tissues with specific receptors.

Hormones

• Hormones are chemical substances and signaling molecules produced and secreted by specific cells.
• Hormones are transported by blood at concentrations of 10-6 to 10-12 M to target structures.
• Target cells have specific receptors for hormones.
• Hormones cause specific responses in distant target tissues.
• Ernest Starling (1866-1927) was a British physiologist.
• Starling isolated secretin in 1902, a substance released into the blood from epithelial cells of the duodenum that stimulates the secretion of pancreatic digestive juice.
• Starling coined the term "hormone" in 1905 meaning "to stir up, impulse," referring to substances released by endocrine glands and carried by the bloodstream.
• Hormones, in extremely small quantities, profoundly influence the function of unconnected body parts.

Endocrine Glands and Hormones

• The hypothalamus releases releasing and inhibitory hormones.
• The anterior pituitary gland secretes growth hormone, adrenocorticotropin, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin.
• The posterior pituitary gland secretes vasopressin (ADH) and oxytocin.
• The thyroid gland produces thyroxine (T4) and triiodothyronine (T3).
• The parathyroid gland secretes parathyroid hormone (PTH).
• The endocrine pancreas produces insulin and glucagon.
• The adrenal cortex produces Glucocorticoids (cortisol, corticosterone) and Mineralocorticoids (aldosterone) and androgens.
• The adrenal medulla secretes catecholamines (epinephrine, norepinephrine, dopamine).
• The testes produce testosterone.
• The ovaries produce estrogens and progesterone.
• The placenta secretes human chorionic gonadotropin (HCG) and human somatomammotropin, estrogens and progesterone.
• The kidney, heart, GIT, pineal gland, and adipocytes all produce hormones also.

Chemical Nature of Hormones

• Steroid hormones are derived from cholesterol and are lipid-soluble.
• Steroid hormones are produced in the adrenal cortex, testes (testosterone), ovaries (estrogen and progesterone), placenta (estrogen and progesterone), and Vitamin D.
• Amine hormones derive from tyrosine.
• Thyroid gland hormones are lipid-soluble amine hormones.
• Adrenal medulla hormones are water-soluble amine hormones.
• Peptide and protein hormones are water-soluble.

Steroid Hormone Secretion

• Steroid hormones are synthesized from cholesterol in mitochondria, smooth endoplasmic reticulum, and cytoplasm.
• Endocrine cells store very little of the final steroid hormone.
• Large quantities of precursor molecules (cholesterol and cholesterol esters) are stored in the cytoplasm.
• A stimulus for secretion activates synthesizing enzymes, which leads to the production and secretion of hormone, diffusion across the cell membrane, then ISF, then blood.
• Most cholesterol comes from plasmatic lipoproteins; less de novo synthesis of cholesterol occurs in endocrine cells.

Amine Hormone Secretion

• Amine hormones derive from tyrosine.
• Catecholamines and thyroid hormones are amine hormones.
• Enzymes in the cytoplasm of endocrine cells form amine hormones.
• Catecholamines are stored in vesicles and released by exocytosis.
• Thyroid hormones incorporated into the large protein thyroglobulin.
• Thyroid hormones are stored in colloid in follicles outside the cells bound to thyroglobulin.
• During secretion, T3 and T4 are cleaved from thyroglobulin and released into capillaries.

Polypeptide and Protein Hormone Secretion

• Polypeptide and protein hormones are formed in the endoplasmic reticulum of endocrine cells.
• The process of forming polypeptide and protein hormones is preprohormone à prohormone à hormone.
• Hormones are stored in secretory vesicles in the cytoplasm until a specific signal causes secretion.
• Polypeptide and protein hormones are released by exocytosis due to increased Ca2+ or cAMP in the cytoplasm.

Hormone Secretion Control

• Negative feedback is a common control mechanism.
• The activity of a gland is influenced by the effects of the hormone it produces or by the hormone itself.
• The responses to the feedback signal oppose the original signal.
• Negative feedback prevents overactivity of the gland.
• Positive feedback is a control mechanism where responses to the feedback signal amplify the original signal.
• Positive feedback does not lead to stability (regulation), but to a progressive change in one direction.
• Simple feedback loops involve a gland, hormone, and effect, in a closed loop.
• Hierarchical control involves multiple levels, such as the cerebral cortex, hypothalamus, anterior pituitary gland, and peripheral gland, each influencing the next in the cascade.

Hormone Transport in Blood

• Water-soluble hormones include peptides and catecholamines.
• Water-soluble hormones are dissolved in plasma.
• Water-soluble hormones are transported in free form (unbound) and diffuse across the capillary wall to target cells.
• Water-soluble hormones have a fast onset of action.
• Lipid-soluble hormones include steroid and thyroid hormones.
• Lipid-soluble hormones are mainly bound to plasma proteins (reservoir).
• Only a small fraction of lipid-soluble hormones is in free form (biologically active form.
• Lipid-soluble hormones have a slower onset of action.
• There is a dynamic equilibrium between protein-bound and free lipid-soluble hormone, which occurs at the target tissue.

Hormone Concentration in Blood

• Hormone concentration depends on the rate of hormone secretion and elimination.
• Elimination mechanisms include endocytosis of the hormone-receptor complex and its intracellular catabolism (peptides), metabolic destruction by enzymes, excretion by the liver to bile, and excretion by the kidney to urine.
• Peptides and catecholamines are more susceptible to enzymes in blood and tissues (short half-life).
• Steroid and thyroid hormones are more resistant to removal and last hours to days.

Hormone Action

• Hormones influence target cells via specific receptors (large proteins).
• The complex hormone-receptor leads to a cascade of reactions → effect (growth, metabolism, development).
• Hormone actions can be stimulatory, inhibitory, permissive, pleiotropic, or have multiplicity.
• Permissive hormone action is when the hormone has no direct effect but must be present for full effect of another hormone
• Pleiotropic is when it produces more than one effect
• Multiplicity is when one process is regulated by more than one hormone.

Receptors

• Receptors are large proteins that are highly specific for a single hormone.
• Cell membrane receptors are for peptides and catecholamines
• Cytoplasm receptors are for steroids.
• The Cell nucleus receptors are for T-hormones.
• Receptor properties include specificity (binding only one type of hormone), affinity (strength of binding), saturation (degree to which RC is occupied), and competition (ability of a molecule to compete with the hormone).

Down- and Up-Regulation

• Down-regulation involves a decrease in the total number of receptors for a given hormone.
• Inactivation of receptors, destruction of receptors, or decreased production of receptors can cause down-regulation.
• Down-regulation results in a response to chronic increases in hormone concentration.
• Up-regulation involves an increase in the total number of receptors for a given hormone.
• Response to chronic decreases in hormone concentration or target cell more sensitive to hormone is a cause for up-regulation.

Signal Transduction Pathways

• Hormone binds to the EC portion of membrane receptor (RC).
• Ionotropic receptors are ligand-gated channels = Catalytic RC.
• It leads to a change in MP.
• G-protein-coupled receptors lead to activation of protein kinase, protein phosphorylation.
• These both lead to cell response.

Channel-Coupled Receptors

• Channel-coupled receptors are ligand-gated channels.
• Binding of messenger to RC.
• It leads to conformational change of RC.
• Next is the Opening of channel, ions diffusion and a Change in MP.
• These both lead to cell response.

Catalytic Receptors

• Catalytic receptors are membrane receptors with enzymatic activity on the cytoplasmic side of the membrane.
• Membrane RC activates the IC enzyme closely associated with RC.
• Receptor guanylyl cyclase natriuretic peptides.
• Receptor tyrosine kinase insulin and growth factors.
• Leptin RC.

G-Protein Coupled Rcs

• G-protein coupled receptors are the largest family of RCs (hundreds).
• Signal molecules are hormones, neurotransmitters, vasoactive peptides and odorants.
• Effectors are enzymes, channels, transporters, contractile proteins.
• G-protein coupled receptors Display GTP-ase activity and regulate synthesis of the second messenger.
• Heterotrimeric G proteins: 3 subunits α, β and y.

Second Messengers

• Extracellular message should be transferred to the intracellular environment
• Second messengers are small, diffusible molecules.
• Second messengers mediate a variety of immediate intracellular events or induce long-term changes.
• Most second messengers are mediated by kinases phosphorylating target proteins (pumps, enzymes, channels, transcription factors).
• Common second messengers include adenylyl cyclase and cyclic AMP, diacylglycerol and inositol triphosphate, and Ca2+.
• Adenylyl cyclase and cAMP.
• Hormones like NE, EPI, ADH and glucagon can affect cAMP.
• Diacylglycerol and inositol triphosphate.
• Hormones like NE, EPI, ACh, ADH can affect ITP.
• Common source of Ca2+ ECF (ligand or voltage-gated channels) and Endoplasmic reticulum.
• Ca2+ common response Calmodulin à calmodulin-dependent protein kinases and Direct effect of Ca2+ on target protein.
• Binding of hormone to receptor leads to hundreds of second messenger molecules which lead to thousand effecter molecules.

Cytoplasmic Receptors

• Steroid hormones, vitamin D act as cytoplasmic receptors.
• List of steps:
• Hormone diffusion across the membrane.
• Binding of hormone to cytoplasmic receptor.
• Dissociation of accompanying protein (chaperon).
• Dimerization of complexes R-H.
• Transport of complex R-H to the nucleus.
• Binding of R-H on HRE sequence of DNA (hormone response element) together wits coactivators and RNA-polymerase.
• Activation of transcription → synthesis of mRNA.
• mRNA diffusion into the cytoplasm.
• Translation activation.
• Protein synthesis.

Nuclear Receptors

• Thyroid Hormones.
• Hormone diffusion across the membrane.
• Binding of T hormone to its nuclear receptor in heterodimer with RXR (retinoid X receptor) – bound to HRE.
• Release of corepressor and binding of coactivator and RNA-polymerase on the complex.
• Activation of transcription → synthesis of mRNA.
• mRNA diffusion into the cytoplasm.
• Initiation of translation.
• Protein synthesis.