The importance of the Thr<SUP>17</SUP> residue of phospholamban as a phosphorylation site under physiological and pathological conditions

• Autores: Mattiazzi, Alicia Ramona; Mundiña-Weilenmann, Cecilia; Vittone, Leticia; Said, María Matilde; Kranias, E. G.
• Año de publicación: 2006
• Idioma: inglés
• Tipo de recurso: reseña artículo
• Materia: Ciencias Médicas; isoprenaline; β-adrenergic stimulation; acidosis; ischemia; serine; threonine; phospholamban; Thr17 site phosphorylation; hypercapnia; pathophysiology; physiology
• Institución: Universidad Nacional de La Plata

The sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA2a) is under the control of an SR protein named phospholamban (PLN). Dephosphorylated PLN inhibits SERCA2a, whereas phosphorylation of PLN at either the Ser¹⁶ site by PKA or the Thr¹⁷ site by CaMKII reverses this inhibition, thus increasing SERCA2a activity and the rate of Ca²⁺ uptake by the SR. This leads to an increase in the velocity of relaxation, SR Ca²⁺ load and myocardial contractility. In the intact heart, β-adrenoceptor stimulation results in phosphorylation of PLN at both Ser¹⁶ and Thr¹⁷ residues. Phosphorylation of the Thr¹⁷ residue requires both stimulation of the CaMKII signaling pathways and inhibition of PP1, the major phosphatase that dephosphorylates PLN. These two prerequisites appear to be fulfilled by β-adrenoceptor stimulation, which as a result of PKA activation, triggers the activation of CaMKII by increasing intracellular Ca²⁺, and inhibits PP1. Several pathological situations such as ischemia-reperfusion injury or hypercapnic acidosis provide the required conditions for the phosphorylation of the Thr¹⁷ residue of PLN, independently of the increase in PKA activity, i.e., increased intracellular Ca²⁺ and acidosis-induced phosphatase inhibition. Our results indicated that PLN was phosphorylated at Thr¹⁷ at the onset of reflow and immediately after hypercapnia was established, and that this phosphorylation contributes to the mechanical recovery after both the ischemic and acidic insults. Studies on transgenic mice with Thr¹⁷ mutated to Ala (PLN-T17A) are consistent with these results. Thus, phosphorylation of the Thr¹⁷ residue of PLN probably participates in a protective mechanism that favors Ca²⁺ handling and limits intracellular Ca²⁺ overload in pathological situations.
Facultad de Ciencias Médicas