Sarcoplasmic reticulum calcium content increases in response to stimulation from catecholamines, explaining why arrhythmias in those with CPVT occur at times when catecholamine levels are elevated. Some suggest that the increased sensitivity to calcium occurs only when the ryanodine receptor is phosphorylated by protein kinase A, while other suggest that the increased sensitivity also occurs under resting conditions.Two theories have been proposed for the underlying mechanism by which mutations in RYR2 promote store-overload induced calcium release: domain unzipping and FKBP12.6 unbinding. Domain unzipping refers to the separation of two important regions of the ryanodine receptor, the N-terminus and the central domain. Through this mechanism, a mutation might destabilise the ryanodine receptors closed state and increase its sensitivity to calcium. A second potential mechanism involves the regulatory protein FKBP12.6, a protein that binds to and stabilises the ryanodine receptor. The binding of FKBP12.6 to the ryanodine receptor is regulated by phosphorylation. Phosphorylation by protein kinase A leads to the dissociation of FKBP12.6, rendering the ryanodine receptor more sensitive to cytosolic calcium. RYR2 mutations may interfere with the binding of FKB12.6 to the ryanodine receptor and thereby increase sensitivity to calcium. It is likely that FKBP12.6 plays a role in some CPVT mutations but not others.RYR2 mutations responsible for CPVT are mainly found in four major domains of the gene. Mutations affecting domains III and IV of the gene (corresponding to the N-terminal region of the protein and cytosolic linker respectively) occur in 46% of cases.
One classification distinguishes "common simple aphthae", accounting for 95% of cases, with 3–6 attacks per year, rapid healing, minimal pain and restriction of ulceration to the mouth; and "complex aphthae", accounting for 5% of cases, where ulcers may be present on the genital mucosa in addition to mouth, healing is slower and pain is more severe. A more common method of classifying aphthous stomatitis is into three variants, distinguished by the size, number and location of the lesions, the healing time of individual ulcers and whether a scar is left after healing (see below). Minor aphthous ulceration
This is the most common type of aphthous stomatitis, accounting for about 80–85% of all cases. This subtype is termed minor aphthous ulceration (MiAU), or minor recurrent aphthous stomatitis (MiRAS). The lesions themselves may be referred to as minor aphthae or minor aphthous ulcers. These lesions are generally less than 10 mm in diameter (usually about 2–3 mm), and affect non-keratinized mucosal surfaces (i.e. the labial and buccal mucosa, lateral borders of the tongue and the floor of the mouth). Usually several ulcers appear at the same time, but single ulcers are possible. Healing usually takes seven to ten days and leaves no scar. Between episodes of ulceration, there is usually an ulcer-free period of variable length. Major aphthous ulceration
This subtype makes up about 10% of all cases of aphthous stomatitis. It is termed major aphthous ulceration (MaAU) or major recurrent aphthous stomatitis (MaRAS).