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Norepinephrine (NE)‐mediated activation of renal sensory nerves is controlled by a crosstalk between the PLC/PKC and adenylyl cyclase/cAMP/PKA transduction pathways
Author(s) -
Kopp Ulla,
Cicha Michael,
Smith Lori
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1078.14
Subject(s) - adenylyl cyclase , crosstalk , protein kinase c , chemistry , microbiology and biotechnology , signal transduction , adcy9 , norepinephrine , sensory system , medicine , adcy10 , endocrinology , neuroscience , biology , dopamine , physics , optics
NE increases and decreases afferent renal nerve activity (ARNA) by activating α 1 ‐adrenoceptors (AR) and α 2 ‐AR, respectively, on renal sensory nerves. Stimulation of α 1 ‐AR activates PLC and PKC leading to increased PGE 2 release which in turn activates the adenylyl cyclase (AC)/cAMP/PKA transduction cascade resulting in increases in substance P release and ARNA. Activation of α 2 ‐AR results in decreased substance P release in association with decreased PGE 2 release. To examine the mechanisms involved in the α 2 ‐mediated reduction in substance P and PGE 2 release, renal pelvises were pretreated with pertussis toxin (PTX), deactivator of G i proteins. PTX enhanced the NE‐induced activation of the renal sensory nerves to a similar extent as an α 2 ‐AR antagonist. These data suggest that NE‐mediated activation of α 2 ‐AR, coupled to G i proteins, leads to reduction in AC activity. In isolated renal pelvises, NE 2 pM failed to increase substance P and PGE 2 release. However in the presence of the AC activator forskolin, 2 pM NE increased renal pelvic release of PGE 2 from 97±8 to 274±30 pg/min and substance P from 5±1 to 10±1 pg/min (P<0.01, n=8). The forskolin‐induced enhancement of the NE‐induced increases in PGE 2 and substance P release were abolished by indomethacin (P<0.01, n=6), the AC inhibitor dideoxyadenosine (n=4) and the PLC inhibitor U73122 (P<0.01, n=9). Likewise, in vivo studies showed that renal pelvic perfusion with forskolin resulted in enhanced ARNA responses to 2 pM NE that were reduced by U73122. Conclusion NE‐mediated activation of renal sensory nerves involves a positive feedback loop consisting of AC facilitating the α 1 ‐AR‐stimulation of PLC/PKC which in turn leads to increased PGE 2 release with subsequent release of substance P and increased ARNA. This is counter regulated by α 2 ‐AR mediated inhibition of AC.