Nuclear receptors function as transcription factors because they can bind to DNA and regulate gene expression.
- Distinguish between the hormone mechanisms of direct gene activation and the second-messenger system
- Receptors that can directly influence gene expression are termed nuclear receptors.
Type I nuclear receptors (found in cytosol) are modified to translocate to the nucleus upon hormone binding.
- Type II nuclear receptors remain in the nucleus where they often create a complex with co-repressor proteins, which are released upon hormone binding.
- Secondary messengers relay signals from receptors on the cell surface to the target molecules.
- The secondary messenger systems bind hormones to a receptor that causes a cascade of changes that leads to actions.
- nuclear receptor: A class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules, as well as to influence gene expression upon activation.
- secondary messenger: Molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus.
- hormone response element: A short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate gene expression.
Hormones can alter cell activity by binding with a receptor. Receptors can either directly influence gene expression and thus cell activity, or induce a secondary signaling cascade that will in turn influence cell activity.
Direct Gene Activation
Receptors that can directly influence gene expression are termed nuclear receptors. Located within the cytosol or nucleus, nuclear receptors are the target of steroid and thyroid hormones that are able to pass through the cell membrane. Nuclear receptors can bind directly to DNA to regulate specific gene expressions and are, therefore, classified as transcription factors.
Nuclear receptors can be classified into two broad classes according to their mechanism of action and their sub-cellular distribution in the absence of ligand. Type I nuclear receptors are located in the cytosol. Upon binding to a hormone the receptor and hormone translocate into the nucleus, and bind to specific sequences of DNA known as hormone response elements (HREs).
Type II receptors are retained in the nucleus. In the absence of ligand, type II nuclear receptors often form a complex with co-repressor proteins. Hormone binding to the nuclear receptor results in dissociation of the co-repressor and the recruitment of co-activator proteins.
Lipid soluble hormones directly regulate gene expression: This figure depicts the mechanism of a class I nuclear receptor (NR) that, in the absence of ligand, is located in the cytosol. Hormone binding to the NR triggers translocation to the nucleus, where the NR binds to a specific sequence of DNA known as a hormone response element (HRE).
For lipophobic hormones that cannot pass the cellular membrane, activity is mediated and amplified within a cell by the action of second messenger mechanisms (molecules that relay signals from receptors on the cell surface to target molecules inside the cell in the cytoplasm or nucleus).
Most hormone receptors are G protein-coupled receptors. Upon hormone binding, the receptor undergoes a conformational change and exposes a binding site for a G-protein. The G-protein is bound to the inner membrane of the cell and consists of three sub-units: alpha, beta, and gamma.
Upon binding to the receptor, it releases a GTP molecule, at which point the alpha sub-unit of the G-protein breaks free from the beta and gamma sub-units and is able to move along the inner membrane until it contacts another membrane-bound protein: the primary effector.
The primary effector then has an action, which creates a signal that can diffuse within the cell. This signal is called the secondary messenger. The secondary messenger may then activate a secondary effector, whose effects depend on the particular secondary messenger system.
Second messenger mechanisms: General schematic of second messenger generation following activation of membrane bound receptors. 1. The agonist activates the membrane-bound receptor. 2. G-protein is activated and produces an effector. 3. The effector stimulates a second messenger synthesis. 4. The second messenger activates an intercellular process.