L24 Steroid receptors

What are the four main classes of hormone/neurotransmitter receptors?

1. Ligand-gated ion channels (e.g., nicotinic receptor)
2. G-protein coupled receptors (GPCRs, e.g., adrenergic receptors)
3. Catalytic (enzyme-linked) receptors (e.g., insulin receptor)
4. Intracellular receptors (e.g., steroid/glucocorticoid receptors)

How do intracellular receptors differ from cell-surface receptors?

Intracellular receptors (e.g., steroid receptors) are in the cytosol or nucleus and, upon activation, act as transcription factors to regulate gene expression.

What is the main glucocorticoid in humans, and where is it produced?

Cortisol, produced in the adrenal cortex.

Outline the CRH-ACTH-cortisol pathway.

CRH from hypothalamus → binds GPCR on pituitary → ACTH released → binds GPCR on adrenal cortex → cortisol synthesized and released → negative feedback on CRH and ACTH

How does CRH trigger ACTH release at the pituitary?

CRH binds its GPCR (Gs-linked) → ↑cAMP → activates PKA → PKA phosphorylates calcium channels → Ca²⁺ influx → ACTH exocytosis.

How does ACTH stimulate cortisol production in adrenal cells?

ACTH binds GPCR (Gs-linked) → ↑cAMP → activates PKA → PKA phosphorylates enzymes for cortisol synthesis and increases their transcription.

Why are steroids and nitric oxide not stored in vesicles?

They are lipid-soluble and diffuse across membranes; production is controlled rather than release

What is the role of HSP90 in steroid receptor signaling?

HSP90 binds inactive cytosolic steroid receptors, stabilizing them; hormone binding releases HSP90, allowing receptor translocation to the nucleus

What is a glucocorticoid response element (GRE)?

DNA sequence in target genes recognized by activated glucocorticoid receptor homodimers to regulate transcription.

How does PKA influence gene transcription?

PKA can translocate to the nucleus and phosphorylate CREB → CREB binds cAMP response elements (CRE) on DNA → activates transcription.

Compare response times of the four receptor types.

Ligand-gated ion channels: very fast (ms), short-acting

• GPCRs: fast (hundreds of ms to min), short- to medium-acting

• Catalytic receptors: moderate (s–h), medium- to long-acting

• Steroid receptors: slow (hours), long-acting

What is the function of glucocorticoids in metabolism?

Catabolic: break down muscle protein → amino acids → gluconeogenesis → ↑blood glucose; also anti-inflammatory.

How do steroid receptors act as transcription factors?

Steroid binds cytosolic receptor → receptor translocates to nucleus → forms homodimer → binds GREs → regulates RNA polymerase and gene transcription.

Can GPCRs and catalytic receptors also regulate gene transcription?

Yes: GPCR via PKA → CREB; catalytic receptors via MAPK → transcription factors.

Name a neurotransmitter that uses an intracellular receptor.

Nitric oxide (NO) → binds soluble guanylate cyclase → ↑cGMP.

Draw the hormone cascade from hypothalamus to cortisol release.

• Hypothalamus: CRH released from neuroendocrine cells → portal blood to pituitary.

• Pituitary: CRH binds Gs-linked GPCR → ↑cAMP → PKA → Ca²⁺ influx → ACTH exocytosis.

• Adrenal cortex: ACTH binds GPCR → ↑cAMP → PKA → phosphorylates cortisol-synthesizing enzymes + ↑enzyme transcription.

• Cortisol release: Lipid-soluble → diffuses into blood → negative feedback on CRH and ACTH.

How does cortisol act on target cells

1. Cortisol diffuses into cytosol → binds glucocorticoid receptor (GR) bound to HSP90.

2. Hormone binding releases HSP90 → receptor translocates to nucleus.

3. GR forms homodimer → binds GREs on DNA.

4. Alters transcription → ↑ or ↓ target gene expression.

How can GPCRs affect gene transcription?

1. GPCR (Gs) → ↑cAMP → activates PKA.

2. PKA enters nucleus → phosphorylates CREB.

3. Phosphorylated CREB binds CREs on DNA → alters transcription of target genes.

Compare how cortisol and insulin are released.

Insulin: stored in vesicles → Ca²⁺ triggers exocytosis.

• Cortisol: made on demand, no vesicles → release controlled by synthesis via ACTH signaling.

Match receptor type to response time & duration.

• Ligand-gated ion channels: ms, short (nerve → nerve, skeletal muscle)

• GPCRs: hundreds ms–min, moderate (heart, smooth muscle, gland secretion)

• Catalytic receptors: s–h, moderate-long (growth factors, hormones)

• Steroid receptors: hours, long-lasting (gene transcription effects)