Role of Ca2+ and protein kinase C in the receptor-mediated activation of Na+/H+ exchange in isolated liver cells

This work aimed to study the relationship between agonist-induced changes in cytosolic free calcium levels, protein kinase C (PKC) activity and intracellular pH in isolated liver cells. We observed that, like α₁-adrenergic agonists, the Ca²⁺-mobilizing vasoactive peptides vasopressin and angiotensin II produced an extracellular-Na⁺-dependent, 5-(N-ethyl-N-isopropyl)amiloride-sensitive, intracellular alkalinization, indicative of Na⁺/H⁺ antiporter activation. Blocking the agonist-induced increase in the intracellular Ca²⁺ concentration using the calcium chelator bis-(o-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid (BAPTA) prevented all types of receptor-mediated intracellular alkalinization. Thus activation of the Na⁺/H⁺ exchanger by either α₁-adrenergic agonists or vasoactive peptides relies on the mobilization of intracellular Ca²⁺. In contrast, only the α₁-adrenergic-agonist-induced alkalinization was dependent on extracellular Ca²⁺. Even though α₁-adrenergic as well as vasoactive peptide agonists stimulated protein kinase C (PKC) activity in isolated liver cells, only the α₁-adrenoreceptor-mediated intracellular alkalinization was dependent on PKC. According to these observations, Ca²⁺-mobilizing agonists appear to activate the Na⁺/H⁺ exchanger by at least two different mechanisms: (1) the α₁-adrenoreceptor-mediated activation that is dependent on extracellular Ca²⁺ and PKC; and (2) vasoactive-peptide-induced alkalinization that is independent of extracellular Ca²⁺ and PKC. The α₁-adrenoreceptor-mediated, PKC-sensitive, activation of the Na⁺/H⁺ exchanger seems to be responsible for the distinct ability of these receptors to elicit the sustained stimulation of hepatic functions.