In contrast to vascular smooth muscle (VSM), cAMP-dependent phosphorylation increases L-type voltage dependent Ca(2+)-channel (L-VDCC) activity in heart. To investigate whether this difference depends on the tissue-specific alpha 1-subunit of the L-VDCC or its regulation by other subunits, we used a Xenopus laevis oocyte expression system. Injection of cAMP into oocytes expressing cardiac alpha 1 or VSM alpha 1 alone had no effect on L-VDCC activity. However, cAMP increased L-VDCC activity 2-fold in oocytes co-expressing cardiac alpha 1 or VSM alpha 1 with the skeletal muscle beta-subunit. These results suggest that the presence of the beta-subunit is required for cAMP-mediated increase of L-VDCC activity and that the characteristics of tissue-specific beta-subunits may explain differential regulation of L-VDCC activity.