Pflügers Archiv : European journal of physiology
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Chronic pain often represents a severe, debilitating condition. Up to 10% of the worldwide population are affected, and many patients are poorly responsive to current treatment strategies. Nociceptors detect noxious conditions to produce the sensation of pain, and this signal is conveyed to the CNS by means of action potentials. ⋯ Several mutations in the SCN9A gene encoding for Nav1.7 have been identified as important cellular substrates for different heritable pain syndromes. This review aims to cover recent progress on our understanding of how biophysical properties of mutant Nav1.7 translate into an aberrant electrogenesis of nociceptors. We also recapitulate the role of Nav1.8 for peripheral pain processing and of additional sodium channelopathies which have been linked to disorders with pain as a significant component.
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In the past years, several hereditary diseases caused by defects in transient receptor potential channels (TRP) genes have been described. This review summarizes our current knowledge about TRP channelopathies and their possible pathomechanisms. Based on available genetic indications, we will also describe several putative pathological conditions in which (mal)function of TRP channels could be anticipated.
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In the cardiovascular system, Ca2+-activated K+-channels (KCa) are considered crucial mediators in the control of vascular tone and blood pressure by modulating the membrane potential and shaping Ca2+-dependent contraction. Vascular smooth muscle cells express the BKCa channel which fine-tunes contractility by providing a negative feedback on Ca2+-elevations. BKCa channel's ion-conducting alpha-subunit is encoded by the KCa1.1 gene, and the accessory and Ca2+-sensitivity modulating beta1-subunit is encoded by the KCNMB1 gene. ⋯ Moreover, the epidemiological studies showed that the presence of the E65K polymorphism in, e.g., BKCa beta1-subunit gene (producing a "gain-of-function") lowers the prevalence for severe hypertension and myocardial infarction. Other SNPs in the BKCa alpha-subunit gene and also in the KCa3.1 gene expressed in the endothelium have been suggested to increase the risk of cardiovascular disease. These findings from sequence analysis of human KCa genes, and epidemiological studies thus provide evidence that genetic variations and mutations in KCa channel genes contribute to human cardiovascular disease.