55. Receptors for signaling for steroid hormones are located at
(1) Plasma membrane
(2) organelle membrane
(3) Intracellular
(4) No receptor

Introduction

Steroid hormones regulate crucial physiological processes by binding to specific receptors. Unlike peptide hormones, steroid hormones are lipophilic, allowing them to cross cell membranes easily. Their receptors have been classically known as intracellular proteins, but emerging evidence reveals complex receptor localization patterns.

Intracellular Localization of Steroid Receptors

• Nucleus and Cytoplasm: The majority (~85-90%) of classical steroid hormone receptors such as estrogen receptor alpha (ERα), progesterone receptor (PR), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) reside predominantly in the nucleus or cytoplasm at rest.

• Function: Upon hormone binding, these receptors dimerize and bind hormone response elements (HREs) in DNA to regulate gene transcription.

Membrane-Associated Steroid Receptors

• A smaller subset (~5%) of steroid receptors localizes to the plasma membrane, where they participate in rapid, non-genomic signaling pathways.

• These membrane receptors can be classical nuclear receptors that traffic to the membrane after post-translational modifications like palmitoylation (attachment of a fatty acid) that promote membrane association.

• Examples include membrane pools of ERα, ERβ, PR, AR, GR, MR, thyroid hormone receptor (THR), and vitamin D receptor (VDR).

• Membrane steroid receptors are associated with lipid rafts or caveolae, help activate second messenger pathways such as calcium flux, cAMP production, kinase activation, and nitric oxide generation.

Mechanisms of Membrane Targeting

• Receptor palmitoylation occurs mainly on receptor monomers and involves enzymes like ZDHHC7 and ZDHHC21.

• Heat shock proteins (e.g., HSP27) assist in receptor folding and membrane trafficking.

• Interaction with scaffold proteins such as caveolin-1 aids localization in caveolae domains.

Integration of Nuclear and Membrane Signaling

• Membrane and nuclear receptor pools can influence each other, coordinating genomic and rapid signaling.

• Membrane signaling modulates transcription factor activity, localization, and gene expression indirectly.

• This crosstalk is critical in various physiological contexts, including metabolism, cardiovascular health, and reproduction.

Summary Table of Steroid Receptor Locations

Correct Answer to the Query

(3) Intracellular — While steroid receptors predominantly function in the nucleus and cytoplasm, some receptor pools do localize to the plasma membrane. The classical and most abundant receptor localization is intracellular.