Little is known regarding factors that induce parasympathetic responsiveness during cardiac development. We demonstrated previously that in atrial cells cultured from chicks 14 days in ovo, transforming growth factor  (TGF) decreased parasympathetic inhibition of beat rate by the muscarinic agonist, carbamylcholine, by 5-fold and decreased expression of G␣ i2 . Here in atrial cells 5 days in ovo, TGF increased carbamylcholine inhibition of beat rate 2.5-fold and increased expression of G␣ i2 . TGF also stimulated G␣ i2 mRNA expression and promoter activity at day 5 while inhibiting them at day 14 in ovo. Over the same time course expression of type I TGF receptors, chick activin receptor-like kinase 2 and 5 increased with a 2.3-fold higher increase in activin receptor-like kinase 2. Constitutively active activin receptor-like kinase 2 inhibited G␣ i2 promoter activity, whereas constitutively active activin receptor-like kinase 5 stimulated G␣ i2 promoter activity independent of embryonic age. In 5-day atrial cells, TGF stimulated the p3TP-lux reporter, which is downstream of activin receptor-like kinase 5 and had no effect on the activity of the pVent reporter, which is downstream of activin receptor-like kinase 2. In 14-day cells, TGF stimulated both pVent and p3TP-lux. Thus TGF exerts opposing effects on parasympathetic response and G␣ i2 expression by activating different type I TGF receptors at distinct stages during cardiac development.A decrease in heart rate in response to parasympathetic stimulation (negative chronotropic response) involves the binding of acetylcholine to M 2 muscarinic receptors and the dissociation of the heterotrimeric G-protein, G i2 , into ␣ i2 and ␥ subunits. The latter activates the inward rectifying K ϩ channel, GIRK1, increasing diastolic depolarization and decreasing heart rate (1). A decrease in the force of contraction in response to muscarinic stimulation (negative inotropic effect) involves the binding of the ␣ i2 subunit to adenylate cyclase followed by a decrease in cAMP production. Several studies support the conclusion that control of G␣ i2 expression regulates the response of the heart to parasympathetic stimulation. The development of parasympathetic responsiveness in the embryonic chick heart is associated with an increase in G␣ i2 expression (2). Furthermore, growth of chick atrial cells in the absence of lipoproteins, which has been shown to result in an increased response to parasympathetic stimulation, is associated with an increase in the expression of G␣ i2 (3, 4). Finally, expression of G␣ i2 in the porcine atrioventricular node resulted in an increase in parasympathetic tone (5).A role for TGF 1 in the development of the parasympathetic response of the heart was suggested by studies in which medium conditioned by co-culture of chick heart cells and ciliary ganglia induced a negative chronotropic response to carbamylcholine in chick heart cells 3.5 days in ovo (dio). This induction of a parasympathetic response was accompanied by an increase in G␣ i...
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