Functional cell biology and molecular pharmacology of ATP sensitive potassium channels.

Adenosine triphosphate (ATP) sensitive potassium channels (K ATP) transduce changes in cellular metabolism into changes in membrane potential. Activation of K ATP channels causes vascular smooth muscle to hyperpolarize. This leads to a relaxation of the pre-contracted muscle. Inhibition of K ATP channels produces membrane depolarisation and reduces the ability of the vascular smooth muscle to hyperpolarize and thereby relax.K ATP channels are inwardly rectifying potassium channels (Kir), which are inhibited by ATP and stimulated by magnesium bound nucleotides. The K ATP channel is an octomeric combination of two different protein subunits. The pore is formed by four Kir6.2 subunits, each of which is associated with a regulatory sulphonylurea receptor (SUR) subunit. K ATP channels are found in a diverse range of tissue and are composed of different Kir and SUR subunits. In smooth muscle, Kir6.2 is the pore forming subunit and SUR2B is the associated regulatory subunit.A structurally diverse group of agents called K ATP channel openers (K ATP COs), have affinity for the SUR of K ATP channels, causing a hyperpolarisation of the cell membrane and a decrease in excitability. K ATP channel openers have a host of potential therapeutic targets, which range from urinary incontinence to obesity.The K ATP COs used in this study can be placed into two categories. The K ATP COs typified by pinacidil are sensitive to L-arginine analogues whereas the K ATP COs typified by cromakalim are insensitive to L-arginine analogues. This sensitivity appears to be independent of nitric oxide synthase (NOS) action as the vasorelaxant and Rb efflux responses to pinacidil are insensitive to the NOS inhibitor L-N5-(1-iminoethyl) ornithine (L-NIO).Pinacidil and cromakalim are believed to have a degree of commonality in how they interact with the K ATP CO binding site on SUR2B. Some parts of pinacidil though are believed to interact with the area of the K ATP CO binding site that recognises L-arginine analogues. In contrast, cromakalim is not believed to interact with this particular region of the K ATP CO binding site, which explains the insensitivity of cromakalim to L-NAME.

Name dc:type.qualificationname

mphil

Level dc:type.qualificationlevel

masters

Grantor dc:publisher.institution

Sheffield Hallam University (United Kingdom).

Year dc:date.issued

2003

Author dc:creator

• Dawson, Nigel.

Advisors dc:contributor.advisor

• Lawson, K
• Hewson, Alan
• Strong, Peter

Language dc:language

en