Chapter 1

TRP Channels: Potential Therapeutic Targets in Blood Disorders

Amritlal Mandal

Abstract

In the recent past, TRP (Transient Receptor Potential) channels have been emerging as promising therapeutic targets to treat different disease conditions. In mammals, 28 TRP channel genes have been reported. TRP channels are nonselective cation channels that respond to different exogenous stimuli, including certain chemicals, osmotic stress, temperature change, etc. Until now, studies on TRP channels in relation to blood disorders are only a handful. Recently, several TRP channels have emerged as potential contributors to different hematological disorders, including blood iron deficiency (TRPML), hereditary hypertension (TRPC3) and blood pressure (BP) regulation (TRPM4). Dysregulated activation of several TRP channel family members has been reported in sickle cell disease (SCD) and in the transgenic mouse model of SCD. In this regard, TRPV1 and TRPA1 channels have been identified as major contributing factors in the rodent SCD pain. Erythropoietin (Epo), a glycated cytokine, secreted by the kidney, plays an important role in red blood cell (RBC) synthesis (erythropoiesis). In murine RBCs, Epo was found to cause TRPC4/TRPC5-mediated calcium entry that certainly appears interesting in order to understand the roles of TRP channels in erythropoiesis. Present evidence indicates functional roles of several TRP channels (TRPC3, TRPC6, TRPV1, TRPV3, TRPV4, TRPA1, TRPM6 and TRPM7) in the progression and/or prevention of fibroproliferative disorders in vital visceral organs including blood vessels and emerges as the main contributor towards several inflammatory processes. TRPV1 channel has gained attention as a required step for Tcell receptor activation by mitogens. Studies involving cell lines derived from hematological and other malignancies indicate TRPV1 could be a potential target for novel cytotoxic therapies. Altered functional roles of several TRP channels have been identified in different classes of hematological malignancies, including leukemias, multiple myelomas (MM) and B-and T-cell lymphomas. TRP channels are the modulators of the hematopoietic cells and control cellular proliferation, differentiation and apoptosis. Thus, TRP channels appear to be promising targets for hematologic cancer therapy and those channels warrant further investigations for novel pharmaceutical and clinical strategies. TRPC1ε has been recently reported as preosteoclasts and important functional roles of TRPC1ε in recruiting a subpopulation of circulating mononuclear cells from blood to bone surface have been described in relation to cellular differentiation. Epigenetic changes in TRPA1 promoter methylation in white blood cells (WBC) have been identified as predictive of human thermal pain sensitivity. An inverse relationship exists between TRPV1 and TRPA1 gene expression in peripheral blood cells with increasing pain symptoms. This chapter reviews different TRP channel expressions in blood cells with a focus on recent advancements of understanding TRP channels as potential therapeutic targets in different blood disorders. This chapter also briefly discusses a few TRP channel modulator drugs that had shown promising results in preclinical studies or in clinical trials. For the sake of simplicity and to stay focused on the present issue of the journal, this chapter briefly discusses the functional roles of some TRP channel proteins that have been emerging as possible drug targets to treat some blood disorders and hematological malignancies.

Total Pages: 1-41 (41)

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