5.6.1: ADH in the Hypothalamus & Posterior Pituitary
ADH is synthetised in the hypothalamus & is transported to the posterior pituitary.
ADH is a nonapeptide produced in the supraoptic and paraventricular nuclei and other areas of the hypothalamus. Its major role is in the regulation of water balance by its effect on the kidneys. ADH is also known as vasopressin because of the vasopressor response to pharmacological doses. Humans and most animals have arginine-vasopressin but pigs have the arginine replaced by a lysine.
ADH is produced from a much larger precursor protein (prepropressophysin). The gene for this precursor is located on human chromosome 20 and is very closely related to the oxytocin gene. These genes probably arose from an ancestral gene as a result of gene duplication about 350 million years ago. The ADH precursor protein contains sequences for three separate peptides into which it is split during transport down the nerve axon to the posterior pituitary. These are ADH, neurophysin & a glycopeptide. The physiological role of these later two peptides is unclear but neurophysin may have a role as a carrier or binding protein within the granules.
The secretory granules containing the ADH and neurophysin move down the axons (axonal transport) to the nerve terminals in the posterior pituitary from where they are secreted into the systemic circulation by a process of exocytosis (involving calcium).
Intravascular ADH has a half-life of only about 15 minutes being rapidly metabolised in the liver and kidney to inactive products.
5.6.2: Renal Actions of ADH
ADH acts on receptors in the basolateral membrane of cells in the cortical and medullary collecting tubules and not on the apical (or luminal) membrane. These membranes have different properties. The apical membrane of these cells is impermeable to water in the absence of ADH but the basolateral membrane is always permeable to water.
ADH initiates its physiological actions by combining with a specific receptor. These are two major types of vasopressin receptors: V1 & V2. The V1 receptors are located on blood vessels and are responsible for the vasopressor action.
The V2 receptors are in the basolateral membrane of the collecting tubule cells in the kidney. Various agonists and antagonists at these receptors have been developed. Desamino-d-arginine vasopressin (dDAVP) is a synthetic V2-agonist which is used clinically in treatment of diabetes insipidus.
The action at the V2 receptor activates adenyl cyclase and cyclic AMP (second messenger) is formed. This initiates a series of events which causes specific vesicles in the cytoplasm to move to and fuse with the apical membrane. The vesicles contain the water channels (aquaporin 2) which are now inserted in the apical (ie luminal) membrane rendering it permeable to water. Water moves into the cell through these channels in response to the osmotic gradient. It passes into the circulation across the basolateral membrane. The basolateral membrane is always freely permeable to water but the apical membrane is permeable only when the water channels are inserted. When intracellular cyclic AMP levels fall, the water channels are removed from the membrane and reform as vesicles.
The cycle of insertion of water channels into then removal from the luminal membrane is referred to as vesicular trafficking and is the final mediator of the ADH-dependent water permeability of the collecting duct cells.
The water channels are membrane proteins called aquaporins. Aquaporin-2 is the protein which is the vasopressin responsive water channel in the collecting duct. It is inserted into the apical membrane in reponse to cyclic AMP. The protein forms a tetrameric complex that spans the membrane and forms a channel which allows rapid water movement in response to an osmolar gradient.
Aquaporins 3 & 4 are the water channels located in the basolateral membrane. Their water permeability is not altered by ADH action and their presence means the basolateral membrane has a continuous water permeability.
Other interesting recent findings in this area are:
- Mercurial diuretics bind to a specific site on aquaporin-2 and block water reabsorption. This is the mechanism of their diuretic action
- The autosomal dominant form of nephrogenic diabetes insipidus is due to mutations in the aquaporin-2 gene
- The X-linked form of nephrogenic diabetes is due to mutations in the gene for the V2 vasopressin receptor. (This receptor gene is on the X chromosome)
- Lithium causes marked down-regulation of aquaporin-2 expression and causes a form of acquired nephrogenic diabetes insipidus