Membrane Receptor Signal Transduction

Proteins, peptides, and charged molecules do not easily diffuse across the cell membrane. Consequently, the cell membrane can serve as a barrier to cell-to-cell communication when such agents are used as neurotransmitters and hormones. This communication barrier is overcome by use of proteins embedded in the cell membrane that function as receptors for signaling molecules. Agents that bind the active site of the receptor protein are called ligands. The ligand, which remains outside the cell, is considered the first messenger. The intracellular agents activated by the ligand are grouped as second messengers.

Binding to Cell Membrane Receptors

Cell surface receptor proteins have active sites that recognize the three-dimensional structure of the ligand. Binding of the ligand to the receptor protein then activates a series of the membrane or intracellular events. These may include activation of a G protein, activation of a kinase or other enzyme, or direct activation of an ion channel. Ultimately, intracellular second messengers will be formed or released and can include cAMP, cGMP, diacylglycerol (DAG), and Ca++ released from the endoplasmic reticulum.

Ligands that bind the receptor and activate it are agonists or activators. Ligands that bind the receptor but do not activate it are called antagonists or blockers. Antagonists are named because the normal agonist cannot bind the receptor and activate it so long as the antagonist is occupying the active site.

Some receptors are physically independent of the ion channel protein. Activation of the receptor activates a G protein. The G protein may directly open the ion channel, or the G protein may activate phospholipase C (PLC), guanylate cyclase, or adenylate cyclase to modify the activity of an ion channel.

Activation of PLC splits phosphatidylinositol 4,5- bisphosphate (PIP2) into diacylglycerol (DAG), which stays in the plasma membrane, and inositol 1,4,5-trisphosphate (IP3), which enters the cytosol. IP3 acts as the second messenger to release Ca++ from the endoplasmic reticulum. Calcium often activates protein kinase C. Calcium actions may be further controlled by the activity of protein calmodulin. DAG activates protein kinase C. Alternatively, hydrolysis of diacylglycerol may produce arachidonic acid, a precursor to prostaglandins and thromboxanes.

Other signal transduction pathways directly activate protein kinases. These kinases, through the phosphorylation of other intracellular proteins, cause protein activation or inactivation. These transduction pathways and the protein G-coupled receptor pathways described above are not exclusive, as cAMP can also activate protein kinases.

The biological advantage of a signal transduction cascade is the amplification of the response during each step of the cascade. The diversity and overlap of second messenger systems also provide multiple opportunities for potentiation and inhibition of signal transduction events.

Although most signal transductions produce immediate effects, the receptor tyrosine kinase mediates the chronic effects of peptides such as growth hormone, insulin-like growth factor I, and numerous other growth factors. Proteins activated by these kinases alter transcription and translation, accounting for chronic growth-related actions.

Recent experiments have shown that steroid hormones and other lipophilic hormones also can activate membrane receptors to produce acute (within minutes) effects. Previously, steroid hormones were thought to work only on nuclear and perinuclear receptors to produce changes that took hours to become evident.

Lipid-Soluble Signal Transduction

The cell membrane is not a barrier to the entry of steroid hormones, thyroid hormone, and the gases nitric oxide (NO) and carbon monoxide (CO). Both NO and CO activate a soluble guanylyl cyclase in the cytosol, leading to the formation of cGMP. NO and CO work mostly as paracrine agents but play a significant role in the regulation of vascular smooth muscle relaxation.

The steroid hormones and thyroid hormone bind to intracellular receptors located within or adjacent to the cell nucleus. The steroid hormone-receptor complex enters the nucleus and acts as a transcription factor, promoting the transcription of specific genes. The transcription/ translation process requires hours or days to exert an effect.