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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

PKC-induced ERK1/2 interactions and downstream effectors in ovine cerebral arteries

Center for Perinatal Biology, Department of Physiology and Pharmacology and Department of Obstetrics and Gynecology, Loma Linda University, School of Medicine, Loma Linda, California

Submitted 16 December 2004 ; accepted in final form 12 March 2005

Both protein kinase C (PKC) and extracellular signal-regulated kinases (ERK1/2) are involved in mediating vascular smooth muscle contraction. We tested the hypotheses that in addition to PKC activation of ERK1/2, by negative feedback ERKs modulate PKC-induced contraction, and that their interactions modulate both thick and thin myofilament pathways. In ovine middle cerebral arteries (MCA), we measured isometric tension and intracellular free calcium concentration ([Ca²⁺]_i) responses to PKC stimulation [phorbol 12,13-dibutyrate (PDBu), 3 x 10^–6 M] in the absence or presence of ERK1/2 inhibition (U-0126, 10^–5 M). After PDBu ± ERK1/2 inhibition, we also examined by Western immunoblot the levels of total and phosphorylated ERK1/2, caldesmon^Ser789, myosin light chain₂₀ (MLC₂₀), and CPI-17. PDBu induced significant increase in tension in the absence of increased [Ca²⁺]_i. PDBu also increased phosphorylated ERK1/2 levels, a response blocked by U-0126. In turn, U-0126 augmented PDBu-induced contractions. PDBu also was associated with significant increases in phosphorylated caldesmon^Ser789 and MLC₂₀ levels, each of which peaked at 5 to 10 min. PDBu also increased phosphorylated CPI-17 levels, which peaked at 2 to 3 min. Rho kinase inhibition (Y-27632, 3 x 10^–7 M) did not alter PDBu-induced contraction. These results support the idea that PKC activation can increase CPI-17 phosphorylation to decrease myosin light chain phosphatase activity. In turn, this increases MLC₂₀ phosphorylation in the thick filament pathway and increases Ca²⁺ sensitivity. In addition, ERK1/2-dependent phosphorylation of caldesmon^Ser789 was not necessary for PDBu-induced contraction and appears not to be involved in the reversal of caldesmon's inhibitory effect on actin-myosin ATPase.

vascular smooth muscle; U-0126; caldesmon; CPI-17; myosin light chain 20

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