Hypertension-associated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport.
The adducin heterodimer is a protein affecting the assembly of the actin-based cytoskeleton. Point mutations in rat adducin alpha (F316Y) and beta (Q529R) subunits are involved in a form of rat primary hypertension (MHS) associated with faster kidney tubular ion transport. A role for adducin in human primary hypertension has also been suggested. By studying the interaction of actin with purified normal and mutated adducin in a cell-free system and the actin assembly in rat kidney epithelial cells (NRK-52E) transfected with mutated rat adducin cDNA, we show that the adducin isoforms differentially modulate: (a) actin assembly both in a cell-free system and within transfected cells; (b) topography of alpha V integrin together with focal contact proteins; and (c) Na-K pump activity at V(max) (faster with the mutated isoforms, 1281 +/- 90 vs 841 +/- 30 nmol K/h.mg pt., P < 0.0001). This co-modulation suggests a role for adducin in the constitutive capacity of the epithelia both to transport ions and to expose adhesion molecules. These findings may also lead to the understanding of the relation between adducin polymorphism and blood pressure and to the development of new approaches to the study of hypertension-associated organ damage.
Tripodi
G
G
Prassis-Sigma Tau Research Institute, Settimo M.se, Milan, Italy.
Valtorta
F
F
Torielli
L
L
Chieregatti
E
E
Salardi
S
S
Trusolino
L
L
Menegon
A
A
Ferrari
P
P
Marchisio
P C
PC
Bianchi
G
G
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000209:etiology*; D017136:Ion Transport; D017354:Point Mutation; D011817:Rabbits; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase; D014162:Transfection; D000099291:Adducins
D000199:Actins; D002148:Calmodulin-Binding Proteins; D000254:Sodium-Potassium-Exchanging ATPase; D000099291:Adducins