title: Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP(3) pathway and the ryanodine receptor.
abstract: The calcium-sensing receptor (CaSR) is a G-coupled protein expressed in renal juxtaglomerular (JG) cells. Its activation stimulates calcium-mediated decreases in cAMP content and inhibits renin release. The postreceptor pathway for the CaSR in JG cells is unknown. In parathyroids, CaSR acts through G(q) and/or G(i). Activation of G(q) stimulates phospholipase C (PLC), and inositol 1,4,5-trisphosphate (IP(3)), releasing calcium from intracellular stores. G(i) stimulation inhibits cAMP formation. In afferent arterioles, the ryanodine receptor (RyR) enhances release of stored calcium. We hypothesized JG cell CaSR activation inhibits renin via the PLC/IP(3) and also RyR activation, increasing intracellular calcium, suppressing cAMP formation, and inhibiting renin release. Renin release from primary cultures of isolated mouse JG cells (n = 10) was measured. The CaSR agonist cinacalcet decreased renin release 56 ± 7% of control (P < 0.001), while the PLC inhibitor U73122 reversed cinacalcet inhibition of renin (104 ± 11% of control). The IP(3) inhibitor 2-APB also reversed inhibition of renin from 56 ± 6 to 104 ± 11% of control (P < 0.001). JG cells were positively labeled for RyR, and blocking RyR reversed CaSR-mediated inhibition of renin from 61 ± 8 to 118 ± 22% of control (P < 0.01). Combining inhibition of IP(3) and RyR was not additive. G(i) inhibition with pertussis toxin plus cinacalcet did not reverse renin inhibition (65 ± 12 to 41 ± 8% of control, P < 0.001). We conclude stimulating JG cell CaSR activates G(q), initiating the PLC/IP(3) pathway, activating RyR, increasing intracellular calcium, and resulting in calcium-mediated renin inhibition.
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Ortiz-Capisano
authors.forename: Mahendranath
authors.initials: M
authors.lastname: Reddy
authors.forename: Mariela
authors.initials: M
authors.lastname: Mendez
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Garvin
authors.forename: William H
authors.initials: WH
authors.lastname: Beierwaltes
mesh_terms: D000818:Animals; D057966:Calcimimetic Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000069449:Cinacalcet; D000242:Cyclic AMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007606:Juxtaglomerular Apparatus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D023421:Models, Animal; D009281:Naphthalenes / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000187:drug effects / Q000378:metabolism*; D012083:Renin / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D057966:Calcimimetic Agents; D004791:Enzyme Inhibitors; D004963:Estrenes; D009281:Naphthalenes; D011760:Pyrrolidinones; D044169:Receptors, Calcium-Sensing; D019837:Ryanodine Receptor Calcium Release Channel; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D037342:Pertussis Toxin; D010738:Type C Phospholipases; D012083:Renin; D002118:Calcium; D000069449:Cinacalcet