DNP 810 Topic 4 Discussion Question Two

Genetic/genomic factors are known to contribute to variability of pharmacologic responses in some patients. How does the variability of responses result in tailoring pharmacologic agents to the care of these patients? Explain. Support your rationale with a minimum of two scholarly sources.

Pharmacological agents that temporarily block brain protein synthesis in a variety of experimental animals have no effect on acquisition of new tasks, yet completely block long-term memory formation. This intervention dissociates the short-term memory associated with training from the storage and retrieval of long-term memory, but does not pinpoint relevant brain regions or specific proteins on which memory formation depends. Rather it sets the stage for future complementary correlative studies, for example, with radioisotopic probes, to identify relevant brain loci and proteins. Proteins provide both neuronal structure (membranes) and catalysts (enzymes) that mediate functional activity. While neurons may last a lifetime and appear to be stable anatomically, their component proteins are in dynamic balance between synthesis and degradation, with half-lives ranging from minutes to weeks.

Protein synthesis takes place primarily in the cell body by translation from RNA, following transcription from DNA. The synapses, at some distance from the cell body, communicate with it by two-way intracellular traffic, termed axoplasmic flow, at rates of a few

DNP 810 Topic 4 Discussion Question Two

millimeters per hour. Assuming that altered behavior is ultimately based on altered synaptic connections, it has been proposed that short-term memory formation relies on post-translational modification of existing synaptic proteins, occurring in milliseconds, while long-term memory requires the slower processes of protein synthesis and axoplasmic transport, thus accounting for delayed formation (consolidation) of long-term memory.

Many pharmacological agents that target voltage-gated K⁺ channels are of proven therapeutic utility or are in various stages of clinical development. The rationale for targeting specific voltage-gated K⁺ channel subtypes for disease management arises from several forms of target validation. Data from genetic and molecular biology studies, including knockout or overexpression of various pore-forming and auxiliary subunits and accessory proteins, have revealed novel roles for K⁺ channels in animal physiology. Moreover, pharmacological characterization of K⁺ channels in normal and pathological cells has been essential in supporting the validation of K⁺ channels in disease. Consequently, agents that modulate various voltage-gated or Ca²⁺-activated K⁺ channels are displaying potential in many phases of drug discovery and early clinical development.

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As a class, most voltage-gated K⁺ channel modulators are primarily focused on the management of cardiac and airway disorders,⁴⁷⁸ although additional therapeutic indications are becoming apparent. Disruptions of normal cardiac rhythm are the leading cause of serious illness and premature death. The key to developing treatments for these conditions is an understanding of the molecular basis of electrical activity in the heart. The heart is a highly specialized organ that maintains a closely choreographed sequence of depolarization, repolarization, and muscle contraction.⁴⁴¹ There are multiple K⁺ channels that contribute to membrane repolarization and hyperpolarization during the cardiac action potential, and, consequently, several potential drug targets have been suggested for the treatment of cardiac electrical or contractile abnormalities. In particular, K_V1.5 subunits are believed to underlie the ultra-rapid delayed rectifier K⁺ current (I_Kur) in atrial myocytes.⁴⁷⁹ Moreover, many class III antiarrhythmic drugs inhibit this channel, and so it has emerged as an attractive drug target for the management of atrial arrhythmias.⁴⁸⁰ Consequently, several novel inhibitors of K_V1.5 are currently being investigated in the clinic as potential antiarrhythmics.

Adding to the pharmacological complexity, it has been shown that the association of K_Vβ1.3 subunits with K_V1.5 can modulate drug block.Other studies have established the importance of the transient outward K⁺ current (I_to) on cardiac function.⁴⁸² This current is relatively large in atrial cells, and its blockade by antiarrhythmic drugs causes a significant increase in the duration of atrial depolarization. The proteins that underlie I_to have been the focus of many studies, and the channel identity is highly species-dependent. In most mammals, I_to appears to be a protein complex containing K_V4.2 and/or K_V4.3, KChIP,⁴⁸³ and, perhaps, additional proteins.^373,484 However in the rabbit, I_to appears to result primarily from K_V1.4 expression.⁴⁸⁵ Adding to the difficulty of validating I_to is the observation that phrixotoxin, which inhibits K_V4.2 and K_V4.3 channels, affects mainly AV node and ventricular function but does not appear to affect atrial repolarization significantly.⁴⁶⁵

Other important delayed rectifier currents in the heart are I_Kr and I_Ks. I_Kr results from hERG association with MiRP1, whereas I_Ks results from K_V7.1 association with minK. However, again there are considerable species differences, and so there is uncertainty surrounding the identity of the actual subunits underlying these native channels. In addition to the complexities of composition and function of native voltage-gated K⁺ channel in heart cells,^486,487 the additional problem of species differences underscores the challenges that are faced in the preclinical development K⁺ channel-modulating antiarrhythmic drugs. Perhaps as a result of these difficulties, many drugs that target voltage-gated K⁺ channels have had limited success in the clinical setting, and this has enhanced the desire to invoke novel strategies and technologies in the search for new class III antiarrhythmic drugs.

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