Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney

Gamba, Gerardo; Miyanoshita, Akihiro; Lombardi, Michael J.; Lytton, Jonathan; Lee, Wen Sen; Hediger, Matthias A.; Hebert, Steven C.

doi:10.1016/s0021-9258(17)32499-7

Cited by 541 publications

(80 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Rat NCC, human WNK4-Flag, human L-WNK1-Δ11-c-Myc, and human KS-WNK1-Δ11-c-Myc have been previously described ( 12 , 18 , 19 ). KS-WNK1-Δ4a, KS-WNK1-2CxS (KS-2CxS), KS-WNK1-6CxS (KS-6CxS), KS-WNK1-5Q (KS-5Q), KS-WNK1-V11A, KS-WNK1-F12A, KS-WNK1-V13A, KS-WNK1-I14A, and KS-WNK1-I15A were made from KS-WNK1-Δ11 using the QuikChange mutagenesis system (Stratagene).…”

Section: Methodsmentioning

confidence: 99%

Role of KLHL3 and dietary K⁺ in regulating KS-WNK1 expression

Ostrosky-Frid

Chávez-Canales

Zhang

et al. 2021

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

The physiological role of the shorter isoform of WNK1 that is exclusively expressed in the kidney (KS-WNK1), with particular abundance in the distal convoluted tubule, remains elusive. KS-WNK1 despite lacking the kinase domain, is nevertheless capable of stimulating the NaCl cotransporter (NCC), apparently through activation of WNK4. It has recently been shown that a less severe form of the Familial Hyperkalemic Hypertension featuring only hyperkalemia is caused by missense mutations in the WNK1 acidic domain that preferentially affect CUL3-KLHL3 E3-induced degradation of KS-WNK1, rather than that of the full-length WNK1 (L-WNK1). Here we show that L-WNK1 is indeed less impacted by the CUL3-KLHL3 E3 ligase complex compared to KS-WNK1. We demonstrate that the unique 30 amino acid amino N-terminal fragment of KS-WNK1 is essential for its activating effect on NCC and recognition by KLHL3. We identify specific amino acid residues in this region critical for the functional effect of KS-WNK1 and KLHL3 sensitivity. To further explore this, we generated KLHL3-R528H knock-in mice that mimic human mutations causing Familial Hyperkalemic Hypertension. These mice revealed that the KLHL3 mutation specifically increased expression of KS-WNK1 in the kidney. We also observed that in wild type mice, expression of KS-WNK1 is only detectable after exposure to low potassium diet. These findings provide new insights into the regulation and function of KS-WNK1 by the CUL3-KLHL3 complex in DCT and indicate that this pathway is regulated by dietary K+ levels.

show abstract

Section: Methodsmentioning

confidence: 99%

Role of KLHL3 and dietary K⁺ in regulating KS-WNK1 expression

Ostrosky-Frid

Chávez-Canales

Zhang

et al. 2021

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…Na + reabsorption in the DCT is highly regulated and affects blood volume and blood pressure. It occurs mainly through the combined actions of the apical Na-Cl cotransporter (NCC) and the basolateral Na + /K + ATPase (Gamba et al, 1994;Plotkin et al, 1996). Thiazide diuretics, for instance, which inhibit NCC function, are widely used in the clinic to treat volume expansion disorders such as congestive heart failure, kidney disease (Sica, 2003;Listed, 2014).…”

Section: Na-cl Cotransporter (Ncc)mentioning

confidence: 99%

Sodium Transporters in Human Health and Disease

Gagnon

Delpire

2021

Front. Physiol.

View full text Add to dashboard Cite

Sodium (Na+) electrochemical gradients established by Na+/K+ ATPase activity drives the transport of ions, minerals, and sugars in both excitable and non-excitable cells. Na+-dependent transporters can move these solutes in the same direction (cotransport) or in opposite directions (exchanger) across both the apical and basolateral plasma membranes of polarized epithelia. In addition to maintaining physiological homeostasis of these solutes, increases and decreases in sodium may also initiate, directly or indirectly, signaling cascades that regulate a variety of intracellular post-translational events. In this review, we will describe how the Na+/K+ ATPase maintains a Na+ gradient utilized by multiple sodium-dependent transport mechanisms to regulate glucose uptake, excitatory neurotransmitters, calcium signaling, acid-base balance, salt-wasting disorders, fluid volume, and magnesium transport. We will discuss how several Na+-dependent cotransporters and Na+-dependent exchangers have significant roles in human health and disease. Finally, we will discuss how each of these Na+-dependent transport mechanisms have either been shown or have the potential to use Na+ in a secondary role as a signaling molecule.

show abstract

“…NKCC1 and NKCC2 monomers share around 60% sequence at protein levels, with NKCC2 slightly smaller than NKCC1 (NKCC1: 1212 amino acids, 131.4 kDa size; and NKCC2: 1099 amino acids, 121.3 kDa). NKCC1 has been experimentally observed to be a homodimer whose expression and composition remains relatively constant across different cell types [ 29 , 31 , 32 , 33 , 34 ]. The phosphorylation of the N terminus has been observed to produce movement in the C terminus as regulation of NKCC1 occurs.…”

Section: Sodium-potassium-chloride Cotransportermentioning

confidence: 99%

Roles of Key Ion Channels and Transport Proteins in Age-Related Hearing Loss

Bazard

Frisina

Acosta

et al. 2021

IJMS

View full text Add to dashboard Cite

The auditory system is a fascinating sensory organ that overall, converts sound signals to electrical signals of the nervous system. Initially, sound energy is converted to mechanical energy via amplification processes in the middle ear, followed by transduction of mechanical movements of the oval window into electrochemical signals in the cochlear hair cells, and finally, neural signals travel to the central auditory system, via the auditory division of the 8th cranial nerve. The majority of people above 60 years have some form of age-related hearing loss, also known as presbycusis. However, the biological mechanisms of presbycusis are complex and not yet fully delineated. In the present article, we highlight ion channels and transport proteins, which are integral for the proper functioning of the auditory system, facilitating the diffusion of various ions across auditory structures for signal transduction and processing. Like most other physiological systems, hearing abilities decline with age, hence, it is imperative to fully understand inner ear aging changes, so ion channel functions should be further investigated in the aging cochlea. In this review article, we discuss key various ion channels in the auditory system and how their functions change with age. Understanding the roles of ion channels in auditory processing could enhance the development of potential biotherapies for age-related hearing loss.

show abstract

Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney

Cited by 541 publications

References 51 publications

Role of KLHL3 and dietary K⁺ in regulating KS-WNK1 expression

Role of KLHL3 and dietary K⁺ in regulating KS-WNK1 expression

Sodium Transporters in Human Health and Disease

Roles of Key Ion Channels and Transport Proteins in Age-Related Hearing Loss

Contact Info

Product

Resources

About

Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney

Cited by 541 publications

References 51 publications

Role of KLHL3 and dietary K+ in regulating KS-WNK1 expression

Role of KLHL3 and dietary K+ in regulating KS-WNK1 expression

Sodium Transporters in Human Health and Disease

Roles of Key Ion Channels and Transport Proteins in Age-Related Hearing Loss

Contact Info

Product

Resources

About

Role of KLHL3 and dietary K⁺ in regulating KS-WNK1 expression

Role of KLHL3 and dietary K⁺ in regulating KS-WNK1 expression