Intracellular Events Also Regulate Mast Cell Degranulation

The cytoplasmic domains of the p and 7 chains of FceRI are associated with protein tyrosine kinases (PTKs). Crosslink-age of the FceRI receptors activates the associated PTKs, resulting in the phosphorylation of tyrosines within the ITAMs of the 7 subunit as well as phosphorylation of residues on the p subunit and on phospholipase C. These phos-phorylation events induce the production of a number of second messengers that mediate the process of degranulation (Figure 16-6).

Within 15 s after crosslinkage of FceRI, methylation of various membrane phospholipids is observed, resulting in an increase in membrane fluidity and the formation of Ca2+ channels. An increase of Ca2+ reaches a peak within 2 min of FceRI crosslinkage (Figure 16-7). This increase is due both to the uptake of extracellular Ca2+ and to a release of Ca2+ from intracellular stores in the endoplasmic reticulum (see Figure 16-6). The Ca2+ increase eventually leads to the formation of arachidonic acid, which is converted into two classes of potent mediators: prostaglandins and leukotrienes (see Figure 16-6). The increase of Ca2+ also promotes the assembly of microtubules and the contraction of microfilaments, both of which are necessary for the movement of granules to the plasma membrane. The importance of the Ca2+ increase in mast-cell degranulation is highlighted by the use of drugs, such as disodium cromoglycate (cromolyn sodium), that block this influx as a treatment for allergies.

Concomitant with phospholipid methylation and Ca2+ increase, there is a transient increase in the activity of membrane-bound adenylate cyclase, with a rapid peak of its reaction product, cyclic adenosine monophosphate (cAMP), reached about 1 min after crosslinkage of FceRI (see Figure 16-7). The effects of cAMP are exerted through the activation of cAMP-dependent

Effects Camp

Secretion Secretion

FIGURE 16-6

Diagrammatic overview of biochemical events in mast-cell activation and degranulation. Allergen crosslinkage of bound IgE results in FceRI aggregation and activation of protein tyrosine kinase (PTK). (1) PTK then phosphorylates phospholipase C, which converts phosphatidylinositol-4,5 bisphosphate (PIP2) into diacylglycerol (DAG) and inositol triphosphate (IP3). (2) DAG activates protein ki nase C (PKC), which with Ca + is necessary for microtubular assembly and the fusion of the granules with the plasma membrane. IP3 is a potent mobilizer of intracellular Ca2+ stores. (3) Crosslinkage of FceRI also activates an enzyme that converts phosphatidylserine (PS) into phos-phatidylethanolamine (PE). Eventually, PE is methylated to form phosphatidylcholine (PC) by the phospholipid methyl transferase enzymes I and II (PMT I and II). (4) The accumulation of PC on the exterior sur face of the plasma membrane causes an increase in membrane fluidity and facilitates the formation of Ca2+ channels. The resulting influx of Ca2+ activates phospholipase A2, which promotes the breakdown of PC into lysophosphatidylcholine (lyso PC) and arachidonic acid. (5) Arachidonic acid is converted into potent mediators: the leuko-trienes and prostaglandin D2. (6) FceRI crosslinkage also activates the membrane adenylate cyclase, leading to a transient increase of cAMP within 15 s. A later drop in cAMP levels is mediated by protein kinase and is required for degranulation to proceed. (7) cAMP-dependent protein kinases are thought to phosphorylate the granule-membrane proteins, thereby changing the permeability of the granules to water and Ca2+. The consequent swelling of the granules facilitates fusion with the plasma membrane and release of the mediators.

protein kinases, which phosphorylate proteins on the granule membrane, thereby changing the permeability of the granules to water and Ca2+ (see Figure 16-6). The consequent swelling of the granules facilitates their fusion with the plasma membrane, releasing their contents. The increase in cAMP is transient and is followed by a drop in cAMP to levels below baseline (see Figure 16-7). This drop in cAMP appears to be necessary for degranulation to proceed; when cAMP levels are increased by certain drugs, the degranulation process is blocked. Several of these drugs are given to treat allergic disorders and are considered later in this section.

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