Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2010 Oct;299(4):F689-701.
doi: 10.1152/ajprenal.00298.2010. Epub 2010 Aug 4.

TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology

Stuart E Dryer  1 , Jochen Reiser
Affiliations
Review

TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology

Stuart E Dryer et al. Am J Physiol Renal Physiol. 2010 Oct.

Abstract

Loss or dysfunction of podocytes is a major cause of glomerular kidney disease. Several genetic forms of glomerular disease are caused by mutations in genes that encode structural elements of the slit diaphragm or the underlying cytoskeleton of podocyte foot processes. The recent discovery that gain-of-function mutations in Ca(2+)-permeable canonical transient receptor potential-6 channels (TRPC6) underlie a subset of familial forms of focal segmental glomerulosclerosis (FSGS) has focused attention on the basic cellular physiology of podocytes. Several recent studies have examined the role of Ca(2+) dynamics in normal podocyte function and their possible contributions to glomerular disease. This review summarizes the properties of TRPC6 and related channels, focusing on their permeation and gating properties, the nature of mutations associated with familial FSGS, and the role of TRPC channels in podocyte cell biology as well as in glomerular pathophysiology. TRPC6 interacts with several proteins in podocytes, including essential slit diaphragm proteins and mechanosensitive large-conductance Ca(2+)-activated K(+) channels. The signaling dynamics controlling ion channel function and localization in podocytes appear to be quite complex.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
A: domain structure of transient receptor potential-6 (TRPC6) channels. Boxes indicate human mutations known to cause focal segmental glomerular sclerosis (FSGS). All of the known disease-causing mutations are located in the cytoplasmic NH2 and COOH terminals of TRPC6. B: immunogold localization of TRPC6, TRPC1, and TRPC5 to podocyte foot processes (arrows). The micrograph of TRPC6 expression also shows that it is present along a primary process.
Fig. 2.
Fig. 2.
Large-conductance Ca2+-activated K+ (BKCa) channels in podocytes. A: topography of the pore-forming subunits of BKCa channels (Slo1 proteins) showing Ca2+-binding domains in the large cytoplasmic COOH terminal. Also shown is a noncanonical SH3 domain that mediates stretch-sensitive gating by interactions with actin-binding proteins. B: colocalization of Slo1 (red) and synaptopodin (green) in a mouse glomerulus revealed by double-label immunofluorescence and a merged image. Areas of colocalization indicate expression in podocytes. Slo1 also appears to be expressed in the mesangium, where there is no synaptopodin. C: model for coordinated activation of TRPC6 and BKCa. Although Ca2+ can permeate TRPC6, it also causes pore blockade and with depolarization TRPC6 behaves as a monovalent cation channel. However, as a result of physical interactions and resulting colocalization, Ca2+ influx through TRPC6 can cause activation of BKCa. This may prevent membrane depolarization, thereby providing a driving force that can sustain Ca2+ infux through TRPC6.
Fig. 3.
Fig. 3.
Models of TRPC6 and BKCa function in podocytes. These channels form a complex with each other in the plasma membrane, which ensures that Ca2+ influx through TRPC6 can cause coordinated activation of BKCa. This serves to prevent membrane depolarization and thereby maintain the Ca2+ permeability of TRPC6. In foot processes (left), these channels also interact with nephrin, podocin (P) and with the underlying actin cytoskeleton, which allows them to function as mechanosensors and to allow the resulting Ca2+ influx to modulate nephrin signaling and cytoskeletal dynamics acting in part through small GTPases and proteins such as Nck and CD2AP (shown schematically as a black circle). BKCa channels are also mechanosensitive through interactions with the cytoskeleton mediated by cortactin (blue circle) or other actin-binding proteins. TRPC6 channels can become active in response to G protein-mediated signaling cascades associated with PLC activation, for example, during angiotensin signaling. The entire slit diaphragm complex may be also regulated by tyrosine kinases such as Fyn. Other TRPC family members are expressed in podocytes, and their functions are unknown. In the cell body (right), they may form heteromeric complexes with TRPC6 and in this way function as Ca2+-store operated channels in G protein signaling cascades associated with PLC activation, possibly in complex with other proteins such as STIM1 and the 1,4,5-trisphosphate (IP3) receptor. Influx of Ca2+ in the cell body can regulate gene expression in podocytes. Excessive Ca2+ influx through TRPC6 channels as a result of mutations or other pathological events can ultimately lead to loss of podocytes through apoptosis as well as detachment from the glomerular basement membrane (GBM). Foot process effacement and podocyte hypertrophy may represent an adaptive response of the remaining podocytes to maintain coverage of the GBM.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Appel D, Kershaw DB, Smeets B, Yuan G, Fuss A, Frye B, Elger M, Kriz W, Floege J, Moeller MJ. Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol 20: 333–343, 2009 - PMC - PubMed
    1. Bao L, Rapin AM, Holmstrand EC, Cox DH. Elimination of the BKCa channel's high-affinity Ca2+ sensitivity. J Gen Physiol 120: 173–189, 2002 - PMC - PubMed
    1. Beisel KW, Rocha-Sanchez SM, Ziegenbein SJ, Morris KA, Kai C, Kawai J, Carninci P, Hayashizaki Y, Davis RL. Diversity of Ca2+-activated K+ channel transcripts in inner ear hair cells. Gene 386: 11–23, 2007 - PubMed
    1. Boulay G. Ca2+-calmodulin regulates receptor-operated Ca2+ entry activity of TRPC6 in HEK-293 cells. Cell Calcium 32: 201–207, 2002 - PubMed
    1. Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24: 349–354, 2000 - PubMed

Publication types

MeSH terms

LinkOut - more resources