Beta adrenergic receptor kinase carboxyl-terminus (also òARKct) is a peptide composed of the last 194 amino acid residues of the carboxyl-terminus of beta adrenergic receptor kinase 1 (òARK1). It binds the òó subunits of G proteins located in the plasma membrane of cells. It is currently an experimental gene therapy for the treatment of heart failure.
During heart failure, the heart is not able to pump enough blood to the rest of the body and will begin to undergo processes in order to compensate for its decreased function. These processes will attempt to increase the heartâÂÂs output; however, the heart may become overstressed and eventually dysfunctional as a result. The sympathetic nervous system increases norepinephrine release to stimulate ò-adrenergic receptors (òARs) located on heart cell (cardiomyocyte) membranes to increase the heartâÂÂs rate and force of contraction. If the heart is already stressed or damaged, this will cause the heart to work above its capacity. Continuous stimulation of the òARs leads to the activation of òARK1 which phosphorylates òARs to decrease their response to norepinephrine and other catecholamines. òARs are downregulated as a result, decreasing the control over the heartâÂÂs rate and force of contraction. A cycle begins as more norepinephrine is produced in an attempt to stimulate the heart to contract.
The òARKct peptide acts by binding to Gòó proteins, competing with òARK1 for the same binding site. òARK1 requires binding to Gòó protein-coupled receptors to be activated. By inhibiting òARK1, òARs will be upregulated back to a normal range. With òAR function restored in a failing heart, the force of contraction increases and the levels of catecholamines and growth factors return to normal. Additionally, when òARs are activated, òARKct will bind Gòó proteins to prevent their interaction with and inhibition of the L-type calcium channels (LCC) present on cardiomyocyte plasma membranes. This increases the flow of calcium ions through the LCCs during depolarization of the cardiomyocyte, increasing calcium levels for contraction to occur. This mechanism has been demonstrated under in vitro conditions and may work with the inhibition of òARK1 to restore òAR function.
The main approach to treatment using òARKct is to insert the gene coding for it into a virus and then infecting cardiomyocytes with it. The virus, containing the òARKct gene, may be injected directly into the left coronary artery or the left ventricular walls following surgical opening of the thorax. A less invasive method for transfer is by using a catheter to inject the virus directly into the left coronary artery without opening the chest cavity.
The use of òARKct gene therapy in humans is still under investigation with no trials currently being carried out. The effectiveness of this therapy has been shown in small animal models including mice, rats, and rabbits. Larger animal models, such as pig hearts, more resemble the human heart and have also demonstrated the benefits of this therapy and its potential use in humans.