ABSTRACT
Cognitive impairment is common in patients with chronic kidney disease. Brain nicotinic acetylcholine receptors modulate cognitive functions, such as learning and memory. Pharmacological cholinergic enhancement is useful in patients with cognitive dysfunction. The major nicotinic acetylcholine receptor subtypes in the brain are heteromeric α4ß2 and homomeric α7 receptors. To study the involvement of neuronal acetylcholine receptors in cognitive impairment in uremic rats, bilateral nephrectomy was performed. 24 weeks after nephrectomy, memory was assessed using the one trial step-down inhibitory avoidance test. Neuronal nicotinic acetylcholine receptors in the brain were studied by radioligand binding, immunoprecipitation, Western blot and sucrose gradient experiments. We demonstrated that rats with severe renal failure show disorders of short term memory. Long term memory was not altered in these rats. The number of functional α4ß2 heteromeric neuronal nicotinic receptors was decreased in the brains of rats with severe renal failure. There was a significant correlation between the degree of renal impairment and the number of heteromeric nicotinic acetylcholine receptors in the brain. The down-regulation of functional α4ß2 receptors in the brains of rats with severe renal failure was not due to a reduction of α4 or ß2 subunit proteins. The number of α7 homomeric neuronal nicotinic acetylcholine receptors was not altered. These findings may have important clinical significance for the management of cognitive impairment in patients with chronic kidney disease.
Subject(s)
Acetylcholine/metabolism , Brain/metabolism , Cognition Disorders/metabolism , Down-Regulation/physiology , Kidney Diseases/metabolism , Neurons/metabolism , Receptors, Nicotinic/metabolism , Uremia/metabolism , Animals , Brain/physiopathology , Brain Diseases, Metabolic/etiology , Brain Diseases, Metabolic/metabolism , Brain Diseases, Metabolic/pathology , Cognition Disorders/etiology , Cognition Disorders/pathology , Disease Models, Animal , Kidney Diseases/complications , Kidney Diseases/pathology , Male , Neurons/pathology , Rats , Rats, Wistar , Uremia/complications , Uremia/pathologyABSTRACT
We have previously demonstrated that the highly conserved R209, that flanks the M1 transmembrane segment of nicotinic acetylcholine (ACh) receptors, is required for the transport of assembled homomeric neuronal α7 nicotinic ACh receptors to the cell surface. In the present paper we show that basic residues at positions 208 and 210 are necessary for the assembly of α7 receptors. On the contrary, a basic residue at position 210 of α3 subunit decreases the assembly of heteromeric neuronal α3ß4 nicotinic ACh receptors. A basic residue at position 210 of the ß4 subunit slightly decreases α3ß4 receptor expression. We conclude that a pre-M1 RRR motif is necessary for the biogenesis of homomeric α-bungarotoxin-sensitive neuronal α7 nicotinic ACh receptors.
