cAMP-independent, G protein-linked inhibition of Na+/H+ exchange in renal brush border by D1 dopamine agonists

Abstract

When D1 dopamine agonists are incubated with renal cortical tissue, Na+/H+ exchange activity is inhibited, presumably due to D1 receptor-mediated stimulation of adenylyl cyclase and subsequent increase in protein kinase A activity. Although the role of adenosine 3',5'-cyclic monophosphate (cAMP) and cAMP-dependent protein kinase in the regulation of Na+/H+ exchange activity is well established, receptors functionally coupled to adenylyl cyclase can regulate Na+/H+ exchange activity independently of changes of cAMP accumulation. The current studies were designed to determine whether D1 agonists can inhibit Na+/H+ exchange activity independently of changes of cAMP accumulation and also to determine the role of G proteins in this process. The D1 agonist, fenoldopam, inhibited Na+/H+ exchange activity in a time-related and concentration-dependent manner. The 50% inhibitory concentration was 5-34 microM. Occupation of the renal D1 receptor mediates this action, since the D1 antagonist, SKF 83742, partially blocks the effect. This action, however, was independent of adenylyl cyclase, protein kinase A, and protein kinase C activity. Inhibition of adenylyl cyclase with dideoxyadenosine or inhibition of protein kinase A and C with the isoquinolines N-(2-guanidinoethyl)-5-isoquinolinesulfonamide hydrochloride (H-4) and 1-(5-isoquinolinesfulfonyl)-2-methylpiperazine (H-7) did not block the effect of fenoldopam on the exchanger. The action of fenoldopam is not due to an amiloride-like action on the exchanger, because kinetic analysis of the inhibitory action was noncompetitive and the effect of fenoldopam was time dependent. The process involved G proteins, since guanosine 5'-O-(2-thiodiphosphate) prevented while guanosine 5'-O-(3-thiotriphosphate) increased the inhibitory effect of fenoldopam.

Asociación y efectos de interacción en los genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R y PTGS2 sobre la hipertensión en población antioqueña

“…Se demostró que el polimorfismo se encuentra en el sitio de unión del microARN miR-504, localizado en la región 3´UTR del gen. El polimorfismo rs686 reside en la parte del 3´UTR complementaria a la secuencia de unión del miR-504; la adecuada complementariedad es crítica en la función de unión del microARN ; el cambio de A a G, reduce la unión del microARN y, por lo tanto, la eficiencia en el expresión del receptor de dopamina(84) este microARN actúa sobrerregulando la expresión del gen, de tal manera que habrá una mayor expresión de los receptores DRD1 en los individuos portadores del alelo A. Los efectos de la dopamina mediados por los receptores D1 (DRD1) se han asociado con la regulación de la presión arterial por medio de la estimulación de la diuresis y natriuresis, y del aumento de la vasodilatación (85,86). La activación de DRD1 por la dopamina responde por el 50 % de la excreción de sodio en condiciones basales (87); por ello, la deficiencia intrarrenal de dopamina puede llevar a hipertensión (88).…”

G Protein-coupled Receptor Kinase 4 (GRK4) Regulates the Phosphorylation and Function of the Dopamine D3 Receptor

“…In this nephron segment, D 3 R stimulation may even result in increased cAMP production because D 3 R may weakly activate adenylyl cyclase 2 (49), which is expressed in the renal proximal tubule (50). The stimulatory G␣ s , which is normally linked to D 1 R and can decrease NHE3 activity by itself (51), and G␣ q/11 , which is involved in the D 1 -like receptor inhibition of Na ϩ /K ϩ -ATPase (52), can also couple to D 3 R (5, 6, 53). D 1 R and D 3 R have been also shown to co-localize and co-immunoprecipitate in WKY rat renal proximal tubule cells (54).…”

Dopamine, hypertension and obesity

“…31 However, it can be also inhibited by a mechanism independent of the cAMP generation, directly through the G protein interaction. 32 Another inhibiting mechanism independent of cAMP is that taking place through PLC activation. 33 Inhibition of this exchanger due to DA is predominantly observed under sodium reload conditions that sensitise kidneys and thus increase their capability to have a natriuresis-inducing response to this stimulus.…”