Characterization of the cyclic nucleotide phosphodiesterase subtypes involved in the regulation of the L-type Ca2+ current in rat ventricular myocytes

• Autor(a) principal: Verde, Ignacio
• Data de Publicação: 1999
• Outros Autores: Vandecasteele, Grégoire, Lezoualc'h, Frank, Fischmeister, Rodolphe
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.6/551

Phosphorylation of cardiac L-type Ca2+ channels by cyclic AMP-dependent protein kinase (PKA) plays a determinant role in the hormonal regulation of myocardial contraction. PKA increases the mean open probability of individual Ca2+ channels which results in an increase in the macroscopic L-type calcium current (ICa) (McDonald et al., 1994). Activation of PKA usually results from an increased production of cyclic AMP by activation of membrane receptors positively coupled to adenylyl cyclase via stimulatory G proteins (Gs). The best documented of such a regulation is the positive inotropic effect of sympathomimetic amines, such as isoprenaline (Hartzell et al., 1991; Hove-Madsen et al., 1996). However, cardiac myocytes, as most other cell types, also possess a negative feedback mechanism to adenylyl cyclase activation which is constituted of the cyclic nucleotide phosphodiesterases (PDEs), a family of enzymes that break down cyclic AMP into 5'-AMP (Beavo, 1995). Cyclic nucleotide PDE activity, at any given location within the cell, will counterbalance the synthesis of cyclic AMP and determine the extent of PKA activation and, hence, of protein phosphorylation. In particular, at the sarcolemmal membrane, this balance between adenylyl cyclase and PDE activities will control the degree of ICa stimulation upon hormonal activation (Fischmeister & Hartzell, 1991; Hove-Madsen et al., 1996). Other factors are involved, such as cyclic AMP compartmentation (Jurevicius & Fischmeister, 1996), PKA tethering to the membrane (Gao et al., 1997), or phosphatase activity (Wiechen et al., 1995). [...]