Phosphorylation calcium channels

Endogenous norepinephrine stimulates cardiac beta receptors. Receptor-linked cAMP-dependent protein kinases phosphorylate calcium channels to increase intracellular calcium. Elevated intracellular calcium increases conduction velocity (phase 0) and decreases the threshold potential in normal SA and AV node cells (see Figure 12.13). Beta blockers slow spontaneous conduction velocity in the SA node by approximately 10-20 percent. In addition, beta blockers can slow conduction velocity while increasing the refractory period of the AV node. These effects control the ventricular rate in atrial fibrillation or flutter and terminate paroxysmal supraventricular tachycardias. They are also safer, although somewhat less effective, than other drugs for suppression of premature ventricular complexes (PVCs). Drugs in this class approved by the FDA for treatment of various arrhythmias include propranolol, acebutolol, and esmolol. Problems with the beta blockers include drowsiness, fatigue, impotence, and depressed ventricular performance. 

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

Protein kinase A (PKA) is a cyclic AMP-dependent protein kinase, a member of a family of protein kinases that are activated by binding of cAMP to their two regulatory subunits, which results in the release of two active catalytic subunits. Targets of PKA include L-type calcium channels (the relevant subunit and site of phosphorylation is still uncertain), phospholam-ban (the regulator of the sarcoplasmic calcium ATPase, SERCA) and key enzymes of glucose and lipid metabolism. 

The effect of stimulation of cardiac adrenoceptors is even more leisurely because several more steps follow activation of the Gs protein by the p-adrenoceptor. For example, to increase the force of cardiac contraction, we have (1) activation of adenylate cyclase by Gas-GTP, (2) formation of cAMP, (3) activation of protein kinase A by the cAMP, then (4) phosphorylation of the calcium channel protein by the kinase. As a result, it takes about 5 to 6 sec from the time the receptors are... 

Alves AM, Symington SB, Lee SH, Clark JM (2010) PKC-dependent phosphorylations modify the action of deltamethrin on rat brain N-type (Cav2.2) voltage-sensitive calcium channel. Pestic Biochem Physiol 97 101-108... 

Phosphorylation of cardiac calcium-channel proteins increases the probability of channel opening during membrane depolarization. It should be noted that cAMP is inactivated by phosphodiesterase. Inhibitors of this enzyme elevate intracellular cAMP concentration and elicit effects resembling those of epinephrine. 

The activation of adenylyl cyclase enables it to catalyze the conversion of adenosine triphosphate (ATP) to 3 5 -cyclic adenosine monophosphate (cAMP), which in turn can activate a number of enzymes known as kinases. Each kinase phosphorylates a specific protein or proteins. Such phosphorylation reactions are known to be involved in the opening of some calcium channels as well as in the activation of other enzymes. In this system, the receptor is in the membrane with its binding site on the outer surface. The G protein is totally within the membrane while the adenylyl cyclase is within the membrane but projects into the interior of the cell. The cAMP is generated within the cell (see Rgure 10.4). 

Autonomic receptors further regulate calcium influx through the sarcolemma (Fig. 15.1). (3-Adrenergic stimulation results in the association of a catalytic subunit of a G protein coupled to the (3-receptor. This stimulates the enzyme adenylyl cyclase to convert ATP to cyclic adenosine monophosphate (cAMP). Increasing cAMP production results in a cAMP-dependent phosphorylation of the L-type calcium channel and a subsequent increase in the probability of the open state of the channel. This translates to an increase in transsarcolemmal calcium influx during phase 2 (the plateau phase) of the cardiac muscle action potential. The effects of transient increases in intracellular levels of cAMP are tightly con-... 

C. The purpose of this question is to clarify the cellular mechanism of analgesia produced by morphine. First, morphine blocks the transmission of nociceptive impulses. In that case, the relevant question is how nociceptive impulses are transmitted via the release of pronociceptive neurotransmitters. The question then is to determine which intracellular process favors a block of release of neurotransmitters. The correct answer is C because calcium is required for neurotransmitter release. Blocking potassium efflux and increasing calcium channel phosphorylation produce functional depolarization and neurotransmitter release. Opioids are coupled to Gj (inhibitory proteins) that decrease cAMP. 

Puri, T.S., Gerhardstein, B.L., Zhao, X.-L., Ladner, M.B. and Hosey, M.M. (1997) Differential effects of subunit interactions on protein kinase A- and C-mediated phosphorylation of L-type calcium channels. Biochemistry 36, 9605-9615. 

Rossie, S. (1999) Regulation of voltage-sensitive sodium and calcium channels by phosphorylation. Advances in Second Messenger and Phosphorylation Research 33, 23 18. 

Erxleben C, Liao Y, Gentile S, Chin D, Gomez-Alegria C, Mori Y, Birnbaumer L, Armstrong DL (2006) Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices. Proc Natl Acad Sci USA 103 3932-3937. 

Martin SW, Butcher AJ, Berrow NS, Richards MW, Paddon RE, Turner DJ, Dolphin AC, Sihra TS, Fitzgerald EM (2006) Phosphorylation sites on calcium channel alphal and beta subunits regulate ERK-dependent modulation of neuronal N-type calcium channels. Cell Calcium 39 275-92... 

Yokoyama CT, Myers SJ, Fu J, Mockus SM, Scheuer T, Catterall WA (2005) Mechanism of SNARE protein binding and regulation of Cav2 channels by phosphorylation of the synaptic protein interaction site. Mol Cell Neurosci 28 1-17 Yokoyama CT, Sheng ZH, Catterall WA (1997) Phosphorylation of the synaptic protein interaction site on N-type calcium channels inhibits interactions with SNARE proteins. J Neurosci 17 6929-38... 

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