Alpha 2-adrenergic receptors regulate Na(+)-H+ exchange via a cAMP-dependent mechanism.
The mechanism by which alpha 2-adrenergic receptors regulate Na(+)-H+ exchange activity in opossum kidney (OK) cells was studied. Because receptors linked to inhibition of adenylate cyclase, like alpha 2-receptors, also can interact with additional signaling mechanisms, we examined specifically the role of adenosine 3',5'-cyclic monophosphate (cAMP) in the signaling pathway controlling Na(+)-H+ activity in OK cells. Parathyroid hormone (PTH), prostaglandin (PGE1), and forskolin, agents that stimulate cAMP production in these cells, inhibited the rate of amiloride-sensitive 22Na+ uptake by up to 40%. Epinephrine and UK 14304, acting through alpha 2-receptors, were able to reverse this inhibition of 22Na+ uptake to near-control levels and also attenuate PTH-, PGE1-, and forskolin-stimulated cAMP accumulation. Likewise, serotonin (5-HT) and SDZ21-009, acting through 5-HT1b receptors, could reverse inhibition of 22Na+ uptake and also attenuate stimulated cAMP accumulation. Neither epinephrine nor serotonin affected the rate of uninhibited 22Na+ uptake. Pertussis toxin pretreatment abolished the effects of alpha 2- and 5-HT1b receptors on both cAMP accumulation and 22Na+ uptake, suggesting that receptor-mediated inhibition of cAMP accumulation is involved in receptor modulation of Na(+)-H+ exchange activity. In contrast, epinephrine was not able to alter the inhibition of 22Na+ uptake mediated by the membrane-permeant cAMP analogues 8-bromo-cAMP and dibutyryl cAMP at any concentration of analogue that significantly inhibited 22Na+ uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
Clarke
J D
JD
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.
Cragoe
E J
EJ
Limbird
L E
LE
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000502:physiology*; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011985:Receptors, Serotonin / Q000502:physiology; D012964:Sodium / Q000037:antagonists & inhibitors / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers
D002352:Carrier Proteins; D005452:Fluoresceins; D005456:Fluorescent Dyes; D010281:Parathyroid Hormone; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D017923:Sodium-Hydrogen Exchangers; C043829:2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein; D012964:Sodium; D000242:Cyclic AMP