Major diseases of the heart, brain, and kidney all have one thing in common: high-blood pressure as a major risk factor. Hypertension afflicts nearly 50 million people in USA, and over 1 billion worldwide. Although hypertension weighs in heavily on world health, its underlying cause for the vast majority of cases is unknown. One of the known components involved in regulating blood pressure is the beta1subunit of the large Ca2+ activated K+ (BK) channel. The beta1 subunit acts to increase the Ca2+- and voltage-sensitivity of the BK channel, and, intriguingly, it is primarily expressed in smooth muscle tissue in vascular walls. Now, Miguel Valverde and colleagues of the Universitat Pompeu Fabra, have found that a specific mutation in the human beta1-subunit gene, KCNMB1, is associated with lower blood pressure. Carrying out a large epidemiological population-based study, the researchers found an very low frequency (3.2%) of the presence of a single nucleotide substitution (G352A), resulting in a glutamic acid-to-lysine change at amino acid position 65, in KCNMB1 in individuals with extremely high diastolic blood pressure as compared to normotensive individuals (21.6%). That this mutation was so rarely found in individuals with such high diastolic pressure suggested that the beta1subunit with this alteration may provide a protective effect against diastolic hypertension. To see if this mutation affects the action of the BK channel, the authors tested mutant beta1 subunit (beta1E65K) in cell culture and showed that beta1E65K alone or in combination with wild-type beta1 subunit further increased the normal Ca2+- and voltage-sensitivity. These data provide biochemical evidence that this mutation alters the activity of the beta1 subunit in a way that affects BK channel activity and thereby impacts on blood pressure. These data provide compelling reason for investigating the therapeutic potential of agents that target the beta1 subu
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Contact: Laurie Goodman
lgoodman@the-jci.org
212-342-4159
Journal of Clinical Investigation
2-Apr-2004