UniProt functional annotation for P37088



	UniProt functional annotation for P37088

UniProt code: P37088.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride. Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells. Plays an essential role in electrolyte and blood pressure homeostasis, but also in airway surface liquid homeostasis, which is important for proper clearance of mucus. Controls the reabsorption of sodium in kidney, colon, lung and eccrine sweat glands. Also plays a role in taste perception. {ECO:0000269|PubMed:24124190, ECO:0000269|PubMed:28710092, ECO:0000269|PubMed:8278374}.

Activity regulation: Activated by WNK1, WNK2, WNK3 and WNK4. {ECO:0000250|UniProtKB:Q61180}.

Subunit: Heterotrimer containing an alpha/SCNN1A, a beta/SCNN1B and a gamma/SCNN1G subunit. An additional delta/SCNN1D subunit exists only in some organisms and can replace the alpha/SCNN1A subunit to form an alternative channel with specific properties (By similarity). Interacts with NEDD4 (via WW domains) (PubMed:11244092, PubMed:11696533, PubMed:12167593, PubMed:23665454). Interacts with NEDD4L (via WW domains) (PubMed:11244092, PubMed:11696533). Interacts with WWP1 (via WW domains) (PubMed:9169421). Interacts with WWP2 (via WW domains) (PubMed:12167593, PubMed:9169421). Interacts with the full-length immature form of PCSK9 (pro-PCSK9) (PubMed:22493497). {ECO:0000250|UniProtKB:Q61180, ECO:0000269|PubMed:11244092, ECO:0000269|PubMed:11696533, ECO:0000269|PubMed:12167593, ECO:0000269|PubMed:22493497, ECO:0000269|PubMed:23665454, ECO:0000269|PubMed:9169421}.

Subcellular location: Apical cell membrane {ECO:0000269|PubMed:22207244, ECO:0000269|PubMed:28130590}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P37089}. Cell projection, cilium {ECO:0000269|PubMed:22207244}. Cytoplasmic granule {ECO:0000269|PubMed:28130590}. Cytoplasm {ECO:0000269|PubMed:28130590}. Cytoplasmic vesicle, secretory vesicle, acrosome {ECO:0000250|UniProtKB:P37089}. Cell projection, cilium, flagellum {ECO:0000250|UniProtKB:P37089}. Note=In the oviduct and bronchus, located on cilia in multi-ciliated cells. In endometrial non-ciliated epithelial cells, restricted to apical surfaces. In epidermis, located nearly uniformly in the cytoplasm in a granular distribution (PubMed:28130590). In sebaceous glands, observed only in the cytoplasmic space in between the lipid vesicles (PubMed:28130590). In eccrine sweat glands, mainly located at the apical surface of the cells facing the lumen (PubMed:28130590). In skin, in arrector pili muscle cells and in adipocytes, located in the cytoplasm and colocalized with actin fibers (PubMed:28130590). In spermatogonia, spermatocytes and round spermatids, located in the cytoplasm (By similarity). Prior to spermiation, location shifts from the cytoplasm to the spermatid tail (By similarity). In spermatozoa, localizes at the acrosome and the central region of the sperm flagellum (By similarity). {ECO:0000250|UniProtKB:P37089, ECO:0000269|PubMed:22207244, ECO:0000269|PubMed:24124190, ECO:0000269|PubMed:28130590}.

Tissue specificity: Expressed in the female reproductive tract, from the fimbrial end of the fallopian tube to the endometrium (at protein level) (PubMed:22207244). Expressed in kidney (at protein level). In the respiratory tract, expressed in the bronchial epithelium (at protein level). Highly expressed in lung. Detected at intermediate levels in pancreas and liver, and at low levels in heart and placenta (PubMed:22207244). in skin, expressed in keratinocytes, melanocytes and Merkel cells of the epidermal sub-layers, stratum basale, stratum spinosum and stratum granulosum (at protein level) (PubMed:28130590). Expressed in the outer root sheath of the hair follicles (at protein level) (PubMed:28130590). Detected in both peripheral and central cells of the sebaceous gland (at protein level) (PubMed:28130590). Expressed by eccrine sweat glands (at protein level) (PubMed:28130590). In skin, also expressed by arrector pili muscle cells and intradermal adipocytes (PubMed:28130590). Isoform 1 and isoform 2 predominate in all tissues. Expression of isoform 3, isoform 4 and isoform 5 is very low or not detectable, except in lung and heart (PubMed:9575806). {ECO:0000269|PubMed:22207244, ECO:0000269|PubMed:28130590, ECO:0000269|PubMed:9575806}.

Induction: By aldosterone. {ECO:0000269|PubMed:11266509}.

Ptm: Ubiquitinated; this targets individual subunits for endocytosis and proteasome-mediated degradation. {ECO:0000250|UniProtKB:P37089}.

Ptm: ENaC cleavage by furin, and subsequently by prostasin (PRSS8), leads to a stepwise increase in the open probability of the channel as a result of release of the alpha and gamma subunit inhibitory tracts, respectively. Interaction of ENaC subunit SCNN1B with BPIFA1 protects ENaC against proteolytic activation. {ECO:0000269|PubMed:18650438}.

Ptm: N-glycosylated. {ECO:0000250|UniProtKB:P37089}.

Disease: Pseudohypoaldosteronism 1, autosomal recessive (PHA1B) [MIM:264350]: A rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. PHA1B is a severe form involving multiple organ systems, and characterized by an often fulminant presentation in the neonatal period with dehydration, hyponatremia, hyperkalemia, metabolic acidosis, failure to thrive and weight loss. {ECO:0000269|PubMed:10586178, ECO:0000269|PubMed:15853823, ECO:0000269|PubMed:18634878}. Note=The disease is caused by variants affecting the gene represented in this entry. The degree of channel function impairment differentially affects the renin-aldosterone system and urinary Na/K ratios, resulting in distinct genotype-phenotype relationships in PHA1 patients. Loss-of-function mutations are associated with a severe clinical course and age-dependent hyperactivation of the renin-aldosterone system. This feature is not observed in patients with missense mutations that reduce but do not eliminate channel function. Markedly reduced channel activity results in impaired linear growth and delayed puberty (PubMed:18634878). {ECO:0000269|PubMed:18634878}.

Disease: Bronchiectasis with or without elevated sweat chloride 2 (BESC2) [MIM:613021]: A debilitating respiratory disease characterized by chronic, abnormal dilatation of the bronchi and other cystic fibrosis-like symptoms in the absence of known causes of bronchiectasis (cystic fibrosis, autoimmune diseases, ciliary dyskinesia, common variable immunodeficiency, foreign body obstruction). Clinical features include sub-normal lung function, sinopulmonary infections, chronic productive cough, excessive sputum production, and elevated sweat chloride in some cases. {ECO:0000269|PubMed:19462466}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Liddle syndrome 3 (LIDLS3) [MIM:618126]: A form of Liddle syndrome, an autosomal dominant disorder characterized by early onset of hypertension, hypokalemic alkalosis, and suppression of plasma renin activity and aldosterone secretion. {ECO:0000269|PubMed:28710092}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: [Isoform 3]: Does not give rise to amiloride-sensitive ion current. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.

Miscellaneous: [Isoform 4]: Amiloride-sensitive ion current is nearly abolished. {ECO:0000305}.

Miscellaneous: [Isoform 5]: Does not give rise to amiloride-sensitive ion current. {ECO:0000305}.

Similarity: Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. SCNN1A subfamily. {ECO:0000305}.

Sequence caution: Sequence=AAH06526.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride. Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells. Plays an essential role in electrolyte and blood pressure homeostasis, but also in airway surface liquid homeostasis, which is important for proper clearance of mucus. Controls the reabsorption of sodium in kidney, colon, lung and eccrine sweat glands. Also plays a role in taste perception. {ECO:0000269\|PubMed:24124190, ECO:0000269\|PubMed:28710092, ECO:0000269\|PubMed:8278374}.


Activity regulation:		Activated by WNK1, WNK2, WNK3 and WNK4. {ECO:0000250\|UniProtKB:Q61180}.
Subunit:		Heterotrimer containing an alpha/SCNN1A, a beta/SCNN1B and a gamma/SCNN1G subunit. An additional delta/SCNN1D subunit exists only in some organisms and can replace the alpha/SCNN1A subunit to form an alternative channel with specific properties (By similarity). Interacts with NEDD4 (via WW domains) (PubMed:11244092, PubMed:11696533, PubMed:12167593, PubMed:23665454). Interacts with NEDD4L (via WW domains) (PubMed:11244092, PubMed:11696533). Interacts with WWP1 (via WW domains) (PubMed:9169421). Interacts with WWP2 (via WW domains) (PubMed:12167593, PubMed:9169421). Interacts with the full-length immature form of PCSK9 (pro-PCSK9) (PubMed:22493497). {ECO:0000250\|UniProtKB:Q61180, ECO:0000269\|PubMed:11244092, ECO:0000269\|PubMed:11696533, ECO:0000269\|PubMed:12167593, ECO:0000269\|PubMed:22493497, ECO:0000269\|PubMed:23665454, ECO:0000269\|PubMed:9169421}.
Subcellular location:		Apical cell membrane {ECO:0000269\|PubMed:22207244, ECO:0000269\|PubMed:28130590}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:P37089}. Cell projection, cilium {ECO:0000269\|PubMed:22207244}. Cytoplasmic granule {ECO:0000269\|PubMed:28130590}. Cytoplasm {ECO:0000269\|PubMed:28130590}. Cytoplasmic vesicle, secretory vesicle, acrosome {ECO:0000250\|UniProtKB:P37089}. Cell projection, cilium, flagellum {ECO:0000250\|UniProtKB:P37089}. Note=In the oviduct and bronchus, located on cilia in multi-ciliated cells. In endometrial non-ciliated epithelial cells, restricted to apical surfaces. In epidermis, located nearly uniformly in the cytoplasm in a granular distribution (PubMed:28130590). In sebaceous glands, observed only in the cytoplasmic space in between the lipid vesicles (PubMed:28130590). In eccrine sweat glands, mainly located at the apical surface of the cells facing the lumen (PubMed:28130590). In skin, in arrector pili muscle cells and in adipocytes, located in the cytoplasm and colocalized with actin fibers (PubMed:28130590). In spermatogonia, spermatocytes and round spermatids, located in the cytoplasm (By similarity). Prior to spermiation, location shifts from the cytoplasm to the spermatid tail (By similarity). In spermatozoa, localizes at the acrosome and the central region of the sperm flagellum (By similarity). {ECO:0000250\|UniProtKB:P37089, ECO:0000269\|PubMed:22207244, ECO:0000269\|PubMed:24124190, ECO:0000269\|PubMed:28130590}.
Tissue specificity:		Expressed in the female reproductive tract, from the fimbrial end of the fallopian tube to the endometrium (at protein level) (PubMed:22207244). Expressed in kidney (at protein level). In the respiratory tract, expressed in the bronchial epithelium (at protein level). Highly expressed in lung. Detected at intermediate levels in pancreas and liver, and at low levels in heart and placenta (PubMed:22207244). in skin, expressed in keratinocytes, melanocytes and Merkel cells of the epidermal sub-layers, stratum basale, stratum spinosum and stratum granulosum (at protein level) (PubMed:28130590). Expressed in the outer root sheath of the hair follicles (at protein level) (PubMed:28130590). Detected in both peripheral and central cells of the sebaceous gland (at protein level) (PubMed:28130590). Expressed by eccrine sweat glands (at protein level) (PubMed:28130590). In skin, also expressed by arrector pili muscle cells and intradermal adipocytes (PubMed:28130590). Isoform 1 and isoform 2 predominate in all tissues. Expression of isoform 3, isoform 4 and isoform 5 is very low or not detectable, except in lung and heart (PubMed:9575806). {ECO:0000269\|PubMed:22207244, ECO:0000269\|PubMed:28130590, ECO:0000269\|PubMed:9575806}.
Induction:		By aldosterone. {ECO:0000269\|PubMed:11266509}.
Ptm:		Ubiquitinated; this targets individual subunits for endocytosis and proteasome-mediated degradation. {ECO:0000250\|UniProtKB:P37089}.
Ptm:		ENaC cleavage by furin, and subsequently by prostasin (PRSS8), leads to a stepwise increase in the open probability of the channel as a result of release of the alpha and gamma subunit inhibitory tracts, respectively. Interaction of ENaC subunit SCNN1B with BPIFA1 protects ENaC against proteolytic activation. {ECO:0000269\|PubMed:18650438}.
Ptm:		N-glycosylated. {ECO:0000250\|UniProtKB:P37089}.
Disease:		Pseudohypoaldosteronism 1, autosomal recessive (PHA1B) [MIM:264350]: A rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. PHA1B is a severe form involving multiple organ systems, and characterized by an often fulminant presentation in the neonatal period with dehydration, hyponatremia, hyperkalemia, metabolic acidosis, failure to thrive and weight loss. {ECO:0000269\|PubMed:10586178, ECO:0000269\|PubMed:15853823, ECO:0000269\|PubMed:18634878}. Note=The disease is caused by variants affecting the gene represented in this entry. The degree of channel function impairment differentially affects the renin-aldosterone system and urinary Na/K ratios, resulting in distinct genotype-phenotype relationships in PHA1 patients. Loss-of-function mutations are associated with a severe clinical course and age-dependent hyperactivation of the renin-aldosterone system. This feature is not observed in patients with missense mutations that reduce but do not eliminate channel function. Markedly reduced channel activity results in impaired linear growth and delayed puberty (PubMed:18634878). {ECO:0000269\|PubMed:18634878}.
Disease:		Bronchiectasis with or without elevated sweat chloride 2 (BESC2) [MIM:613021]: A debilitating respiratory disease characterized by chronic, abnormal dilatation of the bronchi and other cystic fibrosis-like symptoms in the absence of known causes of bronchiectasis (cystic fibrosis, autoimmune diseases, ciliary dyskinesia, common variable immunodeficiency, foreign body obstruction). Clinical features include sub-normal lung function, sinopulmonary infections, chronic productive cough, excessive sputum production, and elevated sweat chloride in some cases. {ECO:0000269\|PubMed:19462466}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Liddle syndrome 3 (LIDLS3) [MIM:618126]: A form of Liddle syndrome, an autosomal dominant disorder characterized by early onset of hypertension, hypokalemic alkalosis, and suppression of plasma renin activity and aldosterone secretion. {ECO:0000269\|PubMed:28710092}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		[Isoform 3]: Does not give rise to amiloride-sensitive ion current. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.
Miscellaneous:		[Isoform 4]: Amiloride-sensitive ion current is nearly abolished. {ECO:0000305}.
Miscellaneous:		[Isoform 5]: Does not give rise to amiloride-sensitive ion current. {ECO:0000305}.
Similarity:		Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. SCNN1A subfamily. {ECO:0000305}.
Sequence caution:		Sequence=AAH06526.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};