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Focal calcium channel modulation

Focal calcium channel modulation description/claims

The present application claims priority to U.S. application Ser. No. 10/678,723 filed Oct. 2, 2003 U.S. Provisional Application No. 60/415,649 as filed on Oct. 2, 2002 the disclosure of which is incorporated herein by reference.

Funding for the present invention was provided in part by the Government of the United States by virtue of Grant Nos. R37 HL36957 and P50 HL52307 from the National Institutes of Health. Accordingly, the Government of the United States has certain rights in and to the invention claimed herein.

Calcium channels include electrically responsive proteins with many important biological functions. The present invention provides a composition, method and system for modulating calcium channels in a focal (rather than non-specific) manner. The invention has a wide spectrum of useful applications including treating a medical condition associated with undesirable calcium channel activity.

There is general recognition that intracellular calcium (Ca.sup.2+) plays an important role in many biological processes such as gene regulation, memory, and cell death. See Muth, J. N. et al. Trends Pharmacol Sci 22, 526-32 (2001); and Carafoli, E. et al. Crit. Rev Biochem Mol Biol 36, 107-260 (2001).

More specifically, there have been reports that abnormal levels of intracellular Ca.sup.2+ foster inappropriate calcium homeostasis in a variety of cells, tissues and organs. Cardiac and neural tissue are thought to be especially sensitive to calcium. As an illustration, certain neurons are believed to undergo abnormal neurotransmitter release, dendritic .sub.Ca.sup.2+ transients and .sub.Ca.sup.2+ action potentials in the presence of inadequate calcium homeostasis.

Many disorders are thought to arise or be exacerbated by inappropriate calcium homeostasis, particularly those impacting the central (CNS) and peripheral (PNS) nervous systems, as well as the endocrine and cardiovascular systems.

Voltage-gated calcium channels are thought to help control the intracellular flow of Ca.sup.2+. These channels (also known as voltage-dependent calcium channels or VDCCs) have been disclosed as being a heterogeneous class of proteins that are responsive to depolarization. The conversion of the intracellular calcium flow by these and other channel proteins is thought to impact a wide spectrum of biological responses. See generally Catterall, W. A. Ann. Rev. Cell Dev. 16: 521 (2000) and U.S. Pat. No. 5,436,128.

Nearly all calcium channels are categorized as T, L, N, P, and Q types. These designations are based largely on electrophysiological and pharmacological properties of the channels. See Catterall, supra; and Dunlap, K. et al. Trends Neurosci. 18:89 (1995).

By way of example, L-type calcium channels are believed to be sensitive to dihydropyridine (DHP) agonists and antagonists as well as certain other compounds. The structure and function of these calcium channels have been disclosed at the molecular level. See eg., Catterall, supra; U.S. Pat. No. 6,365,337; U.S. Pat. Publication No. 2002009772; Perez-Reyes, E. et al. J. Biol. Chem. 267: 1792 (1991); and references cited therein.

See also Ertel, E. A et al. in Neuron 25: 533 (2000) (disclosing various voltage-gated calcium channels with reference to the molecular structure and function of these proteins).

There have been attempts to understand how L-type and other calcium channels are regulated. In this regard, a link between .sub.Ca.sup.2+ channel trafficking and certain guanosine triphosphatase enzymes (GTPases) has been reported. More specifically, interaction between some .sub.Ca.sup.2+ channel subunits and a ras-like GTPase called Gem (also called Kir/Gem) has been disclosed.

The structure and function of Gem has been reported. See Maguire, J. et al. Science 265: 241 (1994) (disclosing the molecular structure of murine and human Gem proteins, for instance). It has been proposed that Gem helps prevent beta. subunit-mediated trafficking of .sub.Ca.sup.2+ channels under appropriate conditions.

There is almost universal belief that the heart maintains an intrinsic rhythm by creating electric stimuli. This leads to contraction of the myocardium. These contractions are the engine that moves blood throughout the vascular system. See generally The Heart and Cardiovascular System. Scientific Foundations. (1986) (Fozzard, H. A. et al. eds) Raven Press, NY.

Certain channel proteins are thought to be closely linked to normal heart function. For instance, genetic mutation of some channel proteins may facilitate or at least aggravate heart disorders such as arrhythmias. As a group, such heart disorders have been referred to as “channelopathies” to denote relationship with abnormal channel protein function. See Marban, E. Nature 415: 213 (2002).

Abnormal channel proteins are thought to impact other heart disorders including hypertrophy, apoptosis, remodeling, fibrillation, angina and in some cases infarcts (“heart attack”). See Bers, D. M. Nature 415, 198-205 (2002); and Marban, E. supra.

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