Regulation of Ion Channels by Phosphorylation

Publisher Summary This chapter discusses the regulation of ion channels by phosphorylation. The chapter focuses on the slow L-type Ca 2+ channel of cardiac muscle for illustrating the important principles that are involved. It is mentioned that considerable attention has been given during the past 25 years to phosphorylation of ion channels as a means whereby the activity of the channels can be regulated or modulated. The chapter discusses several concepts, including cyclic adenosine monophosphate (cyclic AMP/cAMP) stimulation of L-type Ca 2+ channels, inhibition by muscarinic agonists and protein kinase C and calmodulin protein kinase. The enzyme that synthesizes nitric oxide (NO) from L-arginine exists in two basic isoforms—inducible nitric oxide synthase (iNOS or type II) and constitutive nitric oxide synthase (cNOS). It is known that cyclic AMP (cAMP) modulates the functioning of the L-type Ca 2+ channels. Cyclic AMP-dependent phosphorylation also modulates the activity of other channel types. The physiological role played by cyclic GMP (cGMP) on cardiac function is still controversial. cGMP regulates the functioning of the myocardial Ca 2+ slow channels in a manner that is antagonistic to that of cAMP. NO is known to be an important regulator of diverse cellular functions in various tissues. There are several isoforms of phosphodiesterase and some isoforms preferentially degrade cAMP whereas others hydrolyze both cAMP and cGMP relatively equally. Transplanted hearts are exposed to a variety of cytokines during rejection and have an increased NO production and depressed contractility. It has been proposed that muscarinic agonists may also act to inhibit the Ca 2+ channel by stimulation of one or more phosphatases, resulting in dephosphorylation of the channel. It is mentioned that protein kinase C (PK-C) is apparently involved in regulation of the myocardial slow Ca 2+ channels.