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Thick ascending limb: the Na+:K+:2Cl− co-transporter, NKCC2, and the calcium-sensing receptor, CaSR

  • Ion Channels, Receptors and Transporters
  • Published:
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Abstract

The thick ascending limb of Henle’s loop is a nephron segment that is vital to the formation of dilute and concentrated urine. This ability is accomplished by a consortium of functionally coupled proteins consisting of the apical Na+:K+:2Cl− co-transporter, the K+ channel, and basolateral Cl− channel that mediate electroneutral salt absorption. In thick ascending limbs, salt absorption is importantly regulated by the calcium-sensing receptor. Genetic or pharmacological disruption impairing the function of any of these proteins results in Bartter syndrome. The thick ascending limb is also an important site of Ca2+ and Mg2+ absorption. Calcium-sensing receptor activation inhibits cellular Ca2+ absorption induced by parathyroid hormone, as well as passive paracellular Ca2+ transport. The present review discusses these functions and their genetic and molecular regulation.

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Notes

  1. Binding to the same recognition site as an endogenous agonist.

  2. TAL apical membranes express 30- and 70-pS channels, and high-conductance, Ca2+-activated maxi K+ channels. ROMK, the 30-pS channel is absent from apical membranes of ROMK-null mice. The 70-pS channel mediates 80% of the apical K+ conductance. Current thinking suggests that the 70-pS K+ channel is a heterotetramer that includes ROMK, which may be a pore-containing subunit of the 70-pS K+ channels. ROMK1 is expressed in cortical collecting ducts, whereas ROMK2 is present in TAL [13].

  3. Such a problem may contribute to or account for the findings of Desfleurs, who found that increasing basolateral calcium inhibited net calcium absorption without altering Na, Cl, K, or Mg transport by single perfused mouse CALs, [36]. CaSR activation was achieved by increasing basolateral calcium. The CAL, however, is highly permeable to calcium and elevating calcium asymmetrically at the serosal surface increases calcium backflux and results in diminished net calcium absorption regardless of an effect on the CaSR [14]. Under these conditions, it is not possible to distinguish a non-specific effect of diminished driving force from a specific action that can be attributed to the CaSR.

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Acknowledgments

Original studies described here were supported by grants DK 54171 and DK 64635 from the National Institutes of Health to PAF and GG, respectively, CONACYT grant 59992 to GG, and by a grant from the Foundation Leducq for the Transatlantic Network on Hypertension—Renal Salt Handling in the Control of Blood Pressure (GG).

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  1. Molecular Physiology Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

    Gerardo Gamba

  2. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Tlalpan, 14000, Mexico City, Mexico

    Gerardo Gamba

  3. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    Peter A. Friedman

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  1. Gerardo Gamba
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Correspondence to Gerardo Gamba.

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This review is dedicated to the memory of Dr. Steven C. Hebert. Dr. Hebert, our colleague and friend, was a leader in elucidating the mechanism and regulation of salt and water balance by the kidney. He embodied the foresight to anticipate many of the elements contributing to renal homeostasis, an infectious enthusiasm that inspired fellows and colleagues alike, and an open and welcoming collegiality that represents all the best traits of academia.

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Gamba, G., Friedman, P.A. Thick ascending limb: the Na+:K+:2Cl− co-transporter, NKCC2, and the calcium-sensing receptor, CaSR. Pflugers Arch - Eur J Physiol 458, 61–76 (2009). https://doi.org/10.1007/s00424-008-0607-1

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