Differential coupling of dopaminergic D₂ receptors expressed in different cell types: Stimulation of phosphatidylinositol 4,5-bisphosphate hydrolysis in LtK^- fibroblasts, hyperpolarization cytosolic-free Ca²⁺ concentration decrease in GH₄C₁ cells

Dopaminergic D₂ receptors are widely regarded as typical inhibitory receptors, as they both inhibit adenylyl cyclase and decrease the cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) by activating K⁺ channels. A D₂ receptor has recently been cloned (Bunzow, J. R., Van Tol, H. H. M., Grandy, D. K., Albert, P., Salon, J., Christie, M. D., Machida, C. A., Neve, K. A., and Civelli, O. (1988) Nature 336, 783-787) and expressed in two different cell lines, pituitary GH₄C₁ cells and Ltk^- fibroblasts, where it has been shown to induce inhibition of adenylyl cyclase. We have investigated the additional effector systems coupled to this receptor. The responses observed in the two cells lines, which express similar levels of receptors (0.5-1 × 10⁵/cell), were surprisingly different. In GH₄C₁ cells D₂ receptors failed to affect phosphoinositide hydrolysis and induced a decrease of [Ca²⁺]_i. This latter effect appears to be mediated by hyperpolarization, most likely due to the activation of K⁺ channels. In striking contrast, in Ltk^- fibroblasts the D₂ receptor induced a rapid stimulation of inositol(1,4,5)-trisphosphate (+73% at 15 s) followed by the other inositol phosphates, and an immediate increase of [Ca²⁺]_i due to both Ca²⁺ mobilization from internal stores and influx from the extracellular medium. In both GH₄C₁ and Ltk^- cells, the D₂ receptor response was mediated by G protein(s) sensitive to pertussis toxin. The increases of inositol trisphosphate and [Ca²⁺]_i observed in Ltk^- cells required dopamine concentrations only slightly higher than those inhibiting adenylyl cyclase (EG₅₀ = 25, 29, and 11 nM, respectively) and were comparable in magnitude to the responses induced by the endogenous stimulatory receptor agonists, thrombin and ATP. The results demonstrate that in certain cells D₂ receptors are efficiently coupled to the stimulation of phosphoinositide hydrolysis. The nature of receptor responses appears therefore to depend on the specific properties not only of the receptor molecule but also of the cell type in which it is expressed.