Hormone Receptors In and On Cells

Steroid and thyroid hormone receptors are found in the nucleus, cytoplasm, and surrounding plasma membrane (Nilsson et al. 2001; Cato et al. 2002; Bassett et al. 2003). The receptors are categorized by their location as nuclear (in the nucleus), cytoplasmic (in the cytoplasm), or membrane-bound (in the cell membrane). Because of recent advances in understanding the properties and functions of membrane-bound steroid receptors, nuclear steroid receptors - found in the cell’s cytoplasm and nucleus - are often referred to as classical steroid receptors.

In the nucleus, the classic steroid and thyroid receptors mediate gene actions of steroid or thyroid hormones by acting as transcription factors that start gene transcription. When a hormone binds and activates a receptor inside the cell, it forms a hormone receptor complex. The complex then attaches to another complex to form a linked pair called a dimer. These dimers act as transcription factors - proteins that attach to the promoter region of a gene and turn on gene expression, resulting in changes in protein production. The process is relatively slow and can take hours to days for a response to occur.

In contrast, membrane-bound steroid receptors in a cell’s outer covering can trigger fast starting/stopping and quickly reversible responses. Hormones binding to membrane receptors outside the cell send molecular cues through the membrane to activate messenger molecules - called intracellular second messengers - inside the cell. Lightening fast signals travel via chain reactions that characterize these nongenomic processes. The elaborate pathways incorporate signaling systems such as cyclic adenosine monophosphate (cAMP) or kinase enzymes to initiate the cell responses and change cell function within seconds to minutes.

Plasma membrane steroid receptors may be classical steroid receptors expressed in the cell membrane; they may be guanylyl nucleotide regulatory protein (G protein) coupled receptors; or they may have G protein coupled receptor-like structures (Cato et al. 2002; Hammes 2003; Zhu et al. 2003a; Zhu et al. 2003b; Toran-Allerand 2004).

Receptors in the cell’s liquid cytoplasm can control both genomic or non-genomic hormone actions. Inactive (nonhormone-bound) steroid receptors in the cytoplasm may bind a ligand (any molecule that binds to a protein or other molecule), form a hormone-receptor complex, and move to the nucleus to trigger gene transcription. In this case, cytoplasmic receptors mediate genomic actions of the hormone.

Alternatively, the hormone-receptor complex formed after hormones bind and activate inactive receptors in the cytoplasm can interact with other signaling molecules, such as cAMP, in the cell. In this case, cytoplasmic receptors are mediating non-genomic, rapid actions of steroid or thyroid hormones.

Currently, scientists think steroid hormones may interact simultaneously with both the internal cell signaling pathways that mediate rapid cellular responses and with nuclear receptors that mediate gene transcription (Cato et al. 2002; Lu and Cidlowski 2004). For example, estrogen may bind to a membrane-bound estrogen receptor (ER) that triggers intracellular signaling pathways resulting in phosphorylation of inactive classical ERs in the cytoplasm. This step would facilitate estrogen attaching to ER in the cytoplasm, enhancing estrogen stimulation of gene transcription (Cato et al. 2002).

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