A fascinating tail: cGMP activation of aquaporin-1 ion channels

doi:10.1016/S0165-6147(02)02112-0

Trends in Pharmacological Sciences

Volume 23, Issue 12, 1 December 2002, Pages 558-562

https://doi.org/10.1016/S0165-6147(02)02112-0 Get rights and content

Abstract

Aquaporin-1 (AQP1) is a member of the diverse major intrinsic protein family of water and solute channels. AQP1 is known as an osmotic water channel in kidney, brain, vascular system and other tissues, and recently has been demonstrated to function as a cation channel gated by cGMP. Electrophysiology and binding assays implicate direct cGMP binding in the AQP1 C-terminus and sequence similarities with cyclic-nucleotide-gated channels support the idea that the AQP1 C-terminus mediates ion channel activation. In this article, new data show that the AQP1 C-terminus also exhibits homology, at key residues, with the substrate-selectivity subdomain of cyclic nucleotide phosphodiesterases. Distinct pathways for fluxes of water and ions in the tetrameric AQP1 channel indicate an intriguing multifunctional capacity. The physiological role of AQP1 in transmembrane signaling remains to be elucidated for these channels expressed in native tissues.

Section snippets

Protein–protein interactions of ion channels

In the Xenopus oocyte expression system, only a small proportion (∼0.002%) of the AQP1 channels that are present in the membrane appear to be available for cGMP-induced activation of the ionic conductance. However, calculations based on a quantitative model of kidney proximal tubule indicate that this contribution of channels could be physiologically relevant for modulating net Na⁺ reabsorption [8]. Furthermore, this small proportion of ion channels could have profound effects on membrane

Aquaporin-mediated transport

Controversies surround aquaporin-mediated transport, but it is important to recognize that diverse intracellular signaling pathways might influence channel properties, and that the various experimental findings are not necessarily mutually exclusive. The first mammalian aquaporin to be identified as an ion channel was the lens MIP AQP0, a protein that is vital in maintaining the optical clarity of the crystalline lens. Mutations in AQP0 underlie inherited autosomal dominant cataract disease in

C-terminal cyclic-nucleotide-binding domain

An amino acid sequence alignment between the C-terminal domains of AQP1 and CNG channels provides support for the existence of a portion of the cyclic-nucleotide-binding domain (CNBD) in each subunit of the AQP1 channel (Fig. 1c). The CNBD in CNG channels is a complex structure. Based on homology with Escherichia coli catabolite-gene-activator protein (CAP), for which the crystal structure is known [29], it has been suggested that the CNBD in CNG channels consists of a series of β-segments

Concluding remarks

Ion channel function in aquaporins has significance in the regulated control of water and ion fluxes across membranes, and possible functions in ligand-mediated signaling. The essential role of AQP1 in the formation of concentrated urine is evident in transgenic knockout mice that are grossly normal in survival, appearance and organ structure, but susceptible to severe dehydration when deprived of free access to water [40]. Cases of humans with homozygous mutations in AQP1, identified by the

Acknowledgements

Thanks to all the members of the laboratory for their research contributions. Supported by NIH RO1 GM59986 (AJY) and American Heart Association Desert-Mountain Affiliate Predoctoral Award (DB).

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Later, several mechanisms of regulation of the AQP1 channel activities have been described. Cyclic nucleotides (mainly cGMP and indirectly also cAMP) have been shown by Yool group to activate AQP1 channels, both the water channel and the ion channel activity (reviewed in Boassa and Yool, 2002; Yool and Campbell, this issue). Zhang et al. (2007) found that AQP1 water and ion channels function is positively regulated by protein kinase C (PKC).
After a decade of work on the water permeability of red blood cells (RBC) Benga group in Cluj-Napoca, Romania, discovered in 1985 the first water channel protein in the RBC membrane. The discovery was reported in publications in 1986 and reviewed in subsequent years. The same protein was purified by chance by Agre group in Baltimore, USA, in 1988, who called in 1991 the protein CHIP28 (CHannel forming Integral membrane Protein of 28 kDa), suggesting that it may play a role in linkage of the membrane skeleton to the lipid bilayer. In 1992 the Agre group identified CHIP28’s water transport property. One year later CHIP28 was named aquaporin 1, abbreviated as AQP1. In this review the molecular structure–function relationships of AQP1 are presented. In the natural or model membranes AQP1 is in the form of a homotetramer, however, each monomer has an independent water channel (pore). The three-dimensional structure of AQP1 is described, with a detailed description of the channel (pore), the molecular mechanisms of permeation through the channel of water molecules and exclusion of protons. The permeability of the pore to gases (CO₂, NH₃, NO, O₂) and ions is also mentioned. I have also reviewed the functional roles and medical implications of AQP1 expressed in various organs and cells (microvascular endothelial cells, kidney, central nervous system, eye, lacrimal and salivary glands, respiratory apparatus, gastrointestinal tract, hepatobiliary compartments, female and male reproductive system, inner ear, skin). The role of AQP1 in cell migration and angiogenesis in relation with cancer, the genetics of AQP1 and mutations in human subjects are also mentioned. The role of AQP1 in red blood cells is discussed based on our comparative studies of water permeability in over 30 species.
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ANP signaling involves NO production and cGMP formation, but no report on cGMP dependence of AQP1 water permeability has been made so far. AQP1 COOH-terminus has been reported to have a homology with the substrate-selectivity subdomain of cyclic nucleotide phosphodiesterases and with cyclic-nucleotide-gated channels (Boassa and Yool, 2002), predicting the existence of a cyclic nucleotide binding domain. This finding was argued against by another group, predicting instead the existence of a Ca2+-binding site (Section 3.4.3) (Fotiadis et al., 2002).
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Guanosine 3′,5′-cyclic monophosphate (cGMP) produced from guanosine triphosphate (GTP) via soluble or particulate guanylyl cyclase (GC) is an important second messenger for signal transduction within cells. The currently used methods of measuring cGMP including radioimmunoassay and enzyme immunoassay involve the use of radioisotopes or tracers. To develop a cGMP assay that is label-free, non-radioactive, able to detect cGMP directly, and highly specific and sensitive, we used a gold nanoparticle-modified optical fiber (GNOF) conjugated with anti-cGMP antiserum to determine cGMP concentration based on localized surface plasmon resonance (LSPR). The optimal antisera dilution and incubation time for preparing the probe are 1:250 and 2 h, respectively. The sensor shows detection ranges of 0.0025–0.1 and 0.1–100 pmol/ml for acetylated cGMP and cGMP, respectively. The sensitivity for measuring acetylated cGMP is three orders of magnitude higher than that for cGMP. In addition, the biosensor can be stored at 4 °C up to 4 week without losing sensitivity significantly.
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Signaling pathways involving cAMP and cGMP are known to influence salt and water transport in the ciliary epithelium and RPE. Interestingly, while the AQP1 ion conductance is activated by increased cGMP (Anthony et al., 2000; Boassa and Yool, 2002), it has been suggested to be antagonized by intracellular cAMP (Yool and Stamer, 2004). Water channel activity of AQP1 is increased by PKA, suggesting that a cAMP‐responsive redistribution of AQP1 occurs by phosphorylation of AQP1 (Han and Patil, 2000).
Vision is dependent upon the efficient movement of water among and within various structures of the eye. To facilitate the faithful transmission of light rays from the corneal surface to the retinal photoreceptors, the eye is pressurized, having three compartments that are filled with optically transparent fluids: vitreous humor occupies ∼80% of the interior volume of the eye and lies between the posterior face of the lens and the retina; aqueous humor fills the other two compartments, the anterior and posterior chambers, located on either side of the iris. The circulation of aqueous humor from the posterior to the anterior chamber (and then out of the eye) enables the delivery of nutrients and removal of waste products from two specialized avascular tissues, the cornea and crystalline lens that function to focus light onto the retina. The clarity of these two organic lenses, and thus their ability to refract light, is exquisitely dependent upon water homeostasis within and the circulation of aqueous humor around their structures. This chapter reviews data that characterize the role of aquaporins in the movement of water into and out of the eye (aqueous humor dynamics). First, it provides an overview of aquaporin discovery and its molecular structure and function in cellular membranes. Second, it summarizes the specific distribution of aquaporin homologues in the eye. Third, it discusses the specific role of aquaporin channels in aqueous humor dynamics. Finally, the chapter discusses the future direction of aquaporin research in aqueous humor dynamics and the potential of aquaporins as drug targets.

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Trends in Pharmacological Sciences

OpinionA fascinating tail: cGMP activation of aquaporin-1 ion channels

Abstract

Section snippets

Protein–protein interactions of ion channels

Aquaporin-mediated transport

C-terminal cyclic-nucleotide-binding domain

Concluding remarks

Acknowledgements

J. Biol. Chem.

Neuron

J. Mol. Biol.

Curr. Opin. Cell Biol.

Neuron

J. Biol. Chem.

FEBS Lett.

Dev. Biol.

J. Mol. Biol.

Neuron

Neuron

J. Biol. Chem.

Pathophysiology of the aquaporin water channels

Annu. Rev. Physiol.

Aquaporin CHIP: the archetypal molecular water channel

Am. J. Physiol.

Novel roles for aquaporins as gated ion channels

Forskolin stimulation of water and cation permeability in aquaporin 1 water channels

Science

Cloned human aquaporin-1 is a cyclic GMP-gated ion channel

Mol. Pharmacol.

Structure of a glycerol-conducting channel and the basis for its selectivity

Science

New roles for old holes: Ion channel function in aquaporin-1

News Physiol. Sci.

Ion Channels of Excitable Membranes

Opinion
A fascinating tail: cGMP activation of aquaporin-1 ion channels