Hydrophilic Hormones and Second Messenger Systems Notes

Hydrophilic hormones and the plasma membrane

• Hydrophilic (water-soluble) hormones cannot cross the lipid bilayer of the target cell membrane; they dissolve in blood plasma and travel easily in the bloodstream.

• To affect a target cell, they bind to transmembrane receptors on the outside of the cell. This receptor binding triggers a cascade of intracellular events.

First messenger and second messenger concept

• The hormone is the first messenger.

• The cytosolic helper inside the cell is the second messenger.

• This signaling mechanism is called a second messenger system.

• Some neurotransmitters at chemical synapses also utilize second messenger systems.

The cyclic AMP (cAMP) pathway (one common second messenger)

• Hydrophilic hormones such as catecholamines, ACTH, gonadotropins (FSH, LH), thyroid-stimulating hormone (TSH, thyrotropin), parathyroid hormone (PTH), calcitonin, and glucagon use cyclic AMP as a second messenger.

• Mechanism:

  • Hormone binds a receptor on a transmembrane protein, which activates a G protein inside the target cell.

  • The G protein activates the enzyme adenylyl cyclase.

  • Adenylyl cyclase catalyzes the production of cyclic AMP from ATP.

  • The steps described in the transcript can be summarized as:
    $ATP \xrightarrow{\text{adenylyl cyclase}} AMP$
    $AMP \rightarrow cAMP$

  • Cyclic AMP then activates intracellular protein kinases.

  • Activated protein kinases phosphorylate other enzymes (phosphorylation), which can either activate or deactivate those enzymes, depending on the specific enzyme.

• Consequence: The phosphorylation changes alter the cell's metabolic activity.

• Examples of downstream effects:

  • Parathyroid hormone (PTH) acting on osteoblasts decreases hydroxyapatite secretion, thereby preserving calcium and lowering bone density.

  • Follicle-stimulating hormone (FSH) acting on ovarian receptors promotes maturation of ovarian follicles carrying egg cells.

• Termination and termination mechanism:

  • The target cell produces an enzyme called phosphodiesterase, which breaks down cAMP to prevent prolonged signaling.

  • As the hormone is cleared from the system, cyclic AMP becomes unavailable, and the signaling effects cease.

• Not all hydrophilic hormones use the cAMP pathway; some use alternative second messengers.

The phospholipase C pathway (DAG and IP3 as second messengers)

• In some cases, the G protein activates an enzyme called phospholipase C instead of adenylyl cyclase.

• Phospholipase C cleaves membrane phospholipids to yield two second messengers:

  • Diacylglycerol (DAG)

  • Inositol trisphosphate (IP3)

• Reactions and roles:

  • The reaction is described as:
    $PIP<em>2 \xrightarrow{\text{phospholipase C}} DAG + IP</em>3$

  • DAG activates protein kinases, leading to changes in the cell's metabolic activity, similar to the effect of cAMP-activated kinases.

  • IP3 stimulates the opening of calcium ion channels in the endoplasmic reticulum and plasma membrane, allowing Ca^{2+} to diffuse into the cytosol.

  • Calcium ions (Ca^{2+}) can directly activate enzymes or activate protein kinases, producing further metabolic changes.

  • In some cases, calcium ions themselves are considered second messengers.

• The particular second messenger chosen (cAMP, DAG, IP3) depends on the target cell, not on the hormone itself.

  • Example: Thyroid-stimulating hormone (TSH) can use cAMP in some tissues and DAG in others.

  • Similarly, antidiuretic hormone (ADH) can signal via cAMP or IP3 depending on the target cell.

Signal amplification and efficiency

• Circulating levels of hormones are very low relative to other plasma solutes like glucose.

• One hormone molecule can activate a large number of second messenger molecules, and each second messenger can activate many downstream enzymes, amplifying the signal through multiple steps.

• Each activated enzyme can catalyze many chemical reactions, resulting in a large overall metabolic effect from a small initial signal.

• This amplification means glands do not need to produce large amounts of hormone, and target cell membranes do not need to be densely populated with receptors.

Terminology recap and implications

• Remember:

  • The hormone is the first messenger.

  • The intracellular second messenger is the internal helper that propagates the signal.

• Practical implications:

  • The second messenger systems offer multiple amplification points and potential pharmacological targets (e.g., GPCRs, adenylyl cyclase, phospholipase C, phosphodiesterases).

  • Variation in signaling pathways across tissues explains how the same hormone can have diverse effects in different cells.

• Closing note: The second messenger cascades ultimately modulate the cell’s metabolic activity through phosphorylation and other enzyme-activity changes.

Hydrophilic hormones and the plasma membrane

• Hydrophilic (water-soluble) hormones cannot cross the lipid bilayer of the target cell membrane; they dissolve in blood plasma and travel easily in the bloodstream.

• To affect a target cell, they bind to transmembrane receptors on the outside of the cell. This receptor binding triggers a cascade of intracellular events.

First messenger and second messenger concept

• The hormone is the first messenger.

• The cytosolic helper inside the cell is the second messenger.

• This signaling mechanism is called a second messenger system.

• Some neurotransmitters at chemical synapses also utilize second messenger systems.

The cyclic AMP (cAMP) pathway (one common second messenger)

• Hydrophilic hormones such as catecholamines, ACTH, gonadotropins (FSH, LH), thyroid-stimulating hormone (TSH, thyrotropin), parathyroid hormone (PTH), calcitonin, and glucagon use cyclic AMP as a second messenger.

• Mechanism (from beginning of process to end):

  1. Hormone binds to a receptor on a transmembrane protein.

  2. This binding activates a G protein inside the target cell.

  3. The activated G protein then activates the enzyme adenylyl cyclase.

  4. Adenylyl cyclase catalyzes the production of cyclic AMP (cAMP) from ATP.

  • The steps can be summarized as:
    $ATP \xrightarrow{\text{adenylyl cyclase}} AMP$
    $AMP \rightarrow cAMP$

  1. Cyclic AMP then activates intracellular protein kinases.

  2. Activated protein kinases phosphorylate other enzymes (phosphorylation), which can either activate or deactivate those enzymes, depending on the specific enzyme.

  3. Consequence: These phosphorylation changes alter the cell's metabolic activity.

• Examples of downstream effects:

  • Parathyroid hormone (PTH) acting on osteoblasts decreases hydroxyapatite secretion, thereby preserving calcium and lowering bone density.

  • Follicle-stimulating hormone (FSH) acting on ovarian receptors promotes maturation of ovarian follicles carrying egg cells.

• Termination and termination mechanism:

  • The target cell produces an enzyme called phosphodiesterase, which breaks down cAMP to prevent prolonged signaling.

  • As the hormone is cleared from the system, cyclic AMP becomes unavailable, and the signaling effects cease.

• Not all hydrophilic hormones use the cAMP pathway; some use alternative second messengers.

The phospholipase C pathway (DAG and IP3 as second messengers)

• In some cases, the G protein activates an enzyme called phospholipase C instead of adenylyl cyclase.

• Phospholipase C cleaves membrane phospholipids to yield two second messengers:

  • Diacylglycerol (DAG)

  • Inositol trisphosphate (IP3)

• Reactions and roles:

  • The reaction is described as:
    $PIP<em>2 \xrightarrow{\text{phospholipase C}} DAG + IP</em>3$

  • DAG activates protein kinases, leading to changes in the cell's metabolic activity, similar to the effect of cAMP-activated kinases.

  • IP3 stimulates the opening of calcium ion channels in the endoplasmic reticulum and plasma membrane, allowing Ca^{2+} to diffuse into the cytosol.

  • Calcium ions (Ca^{2+}) can directly activate enzymes or activate protein kinases, producing further metabolic changes.

  • In some cases, calcium ions themselves are considered second messengers.

• The particular second messenger chosen (cAMP, DAG, IP3) depends on the target cell, not on the hormone itself.

• Example: Thyroid-stimulating hormone (TSH) can use cAMP in some tissues and DAG in others.

• Similarly, antidiuretic hormone (ADH) can signal via cAMP or IP3 depending on the target cell.

Signal amplification and efficiency

• Circulating levels of hormones are very low relative to other plasma solutes like glucose.

• One hormone molecule can activate a large number of second messenger molecules, and each second messenger can activate many downstream enzymes, amplifying the signal through multiple steps.

• Each activated enzyme can catalyze many chemical reactions, resulting in a large overall metabolic effect from a small initial signal.

• This amplification means glands do not need to produce large amounts of hormone, and target cell membranes do not need to be densely populated with receptors.

Terminology recap and implications

• Remember:

  • The hormone is the first messenger.

  • The intracellular second messenger is the internal helper that propagates the signal.

• Practical implications:

  • The second messenger systems offer multiple amplification points and potential pharmacological targets (e.g., GPCRs, adenylyl cyclase, phospholipase C, phosphodiesterases).

  • Variation in signaling pathways across tissues explains how the same hormone can have diverse effects in different cells.

• Closing note: The second messenger cascades ultimately modulate the cell’