Medical Physiology, 3rd Edition

Nuclear Receptors

Steroid and thyroid hormones enter the cell and bind to members of the nuclear receptor superfamily in the cytoplasm or nucleus

A number of important signaling molecules produce their effects not by binding to receptors on the cell membrane but by binding to nuclear receptors (NRs)—also called intracellular receptors—that can act as transcription regulators, a concept that we will discuss in more depth beginning on p. 81. This family includes receptors for steroid hormones, prostaglandins, vitamin D, thyroid hormones, and retinoic acid (Table 3-6). In addition, this family includes related receptors, known as orphan receptors, whose ligands have yet to be identified. Steroid hormones, vitamin D, and retinoic acid appear to enter the cell by diffusing through the lipid phase of the cell membrane. Thyroid hormones, which are charged amino-acid derivatives, may cross the cell membrane either by diffusion or by carrier-mediated transport. Once inside the cell, these substances bind to intracellular receptors. The ligand-bound receptors are activated transcription factors that regulate the expression of target genes by binding to specific DNA sequences. In addition, steroid hormones can have nongenomic effects (see p. 989). image N3-25

TABLE 3-6

Nuclear Receptors

RECEPTOR

FULL NAME

DIMERIC ARRANGEMENT

GR

Glucocorticoid receptor

GR/GR

MR

Mineralocorticoid receptor

MR/MR

PR

Progesterone receptor

PR/PR

ERα, ERβ

Estrogen receptors

ER/ER

AR

Androgen receptor

AR/AR

VDR

Vitamin D receptor

VDR/RXR

TR

Thyroid hormone receptor

TR/RXR

RAR

Retinoic acid receptor

RAR/RXR

PPARα, PPARγ, PPARδ

Peroxisome proliferation–activated receptors α, γ, δ

PPAR/RXR

FXR

Bile acid receptor

FXR/RXR

LXR

Liver X receptor

LXR/RXR

SXR (or PXR)

Steroid and xenobiotic receptor (pregnane X receptor)

SXR/RXR

CAR

Constitutive androstane receptor

CAR/RXR

RXR, retinoid X receptor.

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Nongenomic Effects of Steroid Hormones

Contributed by Emile Boulpaep, Walter Boron

A theme that is developing in the literature is that certain steroid hormones, when applied to cells in culture, produce biological effects that are too rapid to be mediated by altered gene expression. An example is aldosterone, which—in several cell lines—can cause [Ca2+]i to decrease so rapidly that the effect simply could not be due to altered protein synthesis. Moreover, treatments that block protein synthesis fail to inhibit the ability of aldosterone to lower [Ca2+]i. It is not clear how such rapid, nongenomic effects of steroid hormones may occur. One possibility is that the aldosterone interacts with an alternate receptor (i.e., not the mineralocorticoid receptor that it would normally bind to in the cytoplasm). Another possibility is that aldosterone might bind to the mineralocorticoid receptor, which could have a rapid effect in addition to the traditional, slower genomic effect. Finally, it is possible that the aldosterone nonspecifically interacts with elements of another signaling cascade. Regardless of the mechanism, the rapid action of aldosterone is an exception to the general rule that all of the actions of steroid-type hormones occur by modulation of transcription.