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Articles by J. F Heneghan
Total Records ( 2 ) for J. F Heneghan
  J. F Heneghan , A Akhavein , M. J Salas , B. E Shmukler , L. P Karniski , D. H Vandorpe and S. L. Alper

Nephrolithiasis in the Slc26a6–/– mouse is accompanied by 50–75% reduction in intestinal oxalate secretion with unchanged intestinal oxalate absorption. The molecular identities of enterocyte pathways for oxalate absorption and for Slc26a6-independent oxalate secretion remain undefined. The reported intestinal expression of SO42– transporter SLC26A2 prompted us to characterize transport of oxalate and other anions by human SLC26A2 and mouse Slc26a2 expressed in Xenopus oocytes. We found that hSLC26A2-mediated [14C]oxalate uptake (K1/2 of 0.65 ± 0.08 mM) was cis-inhibited by external SO42– (K1/2 of 3.1 mM). hSLC26A2-mediated bidirectional oxalate/SO42– exchange exhibited extracellular SO42– K1/2 of 1.58 ± 0.44 mM for exchange with intracellular [14C]oxalate, and extracellular oxalate K1/2 of 0.14 ± 0.11 mM for exchange with intracellular 35SO42–. Influx rates and K1/2 values for mSlc26a2 were similar. hSLC26A2-mediated oxalate/Cl exchange and bidirectional SO42–/Cl exchange were not detectably electrogenic. Both SLC26A2 orthologs exhibited nonsaturable extracellular Cl dependence for efflux of intracellular [14C]oxalate, 35SO42–, or 36Cl. Rate constants for 36Cl efflux into extracellular Cl, SO42–, and oxalate were uniformly 10-fold lower than for oppositely directed exchange. Acidic extracellular pH (pHo) inhibited all modes of hSLC26A2-mediated anion exchange. In contrast, acidic intracellular pH (pHi) selectively activated exchange of extracellular Cl for intracellular 35SO42– but not for intracellular 36Cl or [14C]oxalate. Protein kinase C inhibited hSLC26A2 by reducing its surface abundance. Diastrophic dysplasia mutants R279W and A386V of hSLC26A2 exhibited similar reductions in uptake of both 35SO42– and [14C]oxalate. A386V surface abundance was reduced, but R279W surface abundance was at wild-type levels.

  J. F Heneghan , T Mitra Ganguli , L. F Stanish , L Liu , R Zhao and A. R. Rittenhouse

In superior cervical ganglion (SCG) neurons, stimulation of M1 receptors (M1Rs) produces a distinct pattern of modulation of N-type calcium (N-) channel activity, enhancing currents elicited with negative test potentials and inhibiting currents elicited with positive test potentials. Exogenously applied arachidonic acid (AA) reproduces this profile of modulation, suggesting AA functions as a downstream messenger of M1Rs. In addition, techniques that diminish AA's concentration during M1R stimulation minimize N-current modulation. However, other studies suggest depletion of phosphatidylinositol-4,5-bisphosphate during M1R stimulation suffices to elicit modulation. In this study, we used an expression system to examine the physiological mechanisms regulating modulation. We found the β subunit (CaVβ) acts as a molecular switch regulating whether modulation results in enhancement or inhibition. In human embryonic kidney 293 cells, stimulation of M1Rs or neurokinin-1 receptors (NK-1Rs) inhibited activity of N channels formed by CaV2.2 and coexpressed with CaVβ1b, CaVβ3, or CaVβ4 but enhanced activity of N channels containing CaVβ2a. Exogenously applied AA produced the same pattern of modulation. Coexpression of CaVβ2a, CaVβ3, and CaVβ4 recapitulated the modulatory response previously seen in SCG neurons, implying heterogeneous association of CaVβ with CaV2.2. Further experiments with mutated, chimeric CaVβ subunits and free palmitic acid revealed that palmitoylation of CaVβ2a is essential for loss of inhibition. The data presented here fit a model in which CaVβ2a blocks inhibition, thus unmasking enhancement. Our discovery that the presence or absence of palmitoylated CaVβ2a toggles M1R- or NK-1R–mediated modulation of N current between enhancement and inhibition identifies a novel role for palmitoylation. Moreover, these findings predict that at synapses, modulation of N-channel activity by M1Rs or NK-1Rs will fluctuate between enhancement and inhibition based on the presence of palmitoylated CaVβ2a.

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