BioMed Central Page 1 of 2 (page number not for citation purposes) BMC Pharmacology Open Access Oral presentation Melanocytes: interface of cell biology and pathobiology with a focus on nitric oxide and cGMP signaling Krassimira Ivanova* 1 , Pranab Kumar Das 2 and Rupert Gerzer 1 Address: 1 Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany and 2 Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands Email: Krassimira Ivanova* - krassimira.ivanova@dlr.de * Corresponding author Human epidermal melanocytes represent a crucial protec- tive barrier against UV irradiation and oxidative stress by generating the radical scavenging pigment melanin. Mela- nin is also known to act as a photosensitizer that generates active oxygen species upon UV irradiation, which may ini- tiate hypopigmentary disorders (e.g., vitiligo) as well as UV-induced oncogene cell transformation. Finally, melanocytes in vivo are permanently targeted by environ- mental mechanical stimuli. For human melanocytes, it has been shown that the nitric oxide (NO)-soluble guanylyl cyclase (sGC) pathway, through the activation of cGMP-dependent protein kinase, is involved in UVB-induced melanogenesis [1]. In previous studies we found that different guanylyl cyclase (GC) isoforms are responsible for cGMP synthesis in melanocytic cells. Normal human melanocytes and non- metastatic melanoma cell lines predominantly express sGC, which appears to be associated with melanogenesis, whereas absence of NO-sensitive GC, but upregulated activities of the membrane isoforms GC-A and GC-B were found in highly metastatic phenotypes [2]. We also showed that NO can induce perturbation of melanocyte- extracellular matrix interactions, which may contribute to loss of melanocytes or melanoma metastasis [3,4]. The NO effects appear to be modulated partly by cGMP [4]. In the frame of the current space exploration, we further have investigated the regulation of cGMP levels in melanocytes at altered gravity conditions. Our studies indicate that cultured melanocytes and non-metastatic melanoma cells respond to long-time exposure to hyper- gravity (up to 5 × g for 24 h) with an elevated cGMP efflux under conditions where phosphodiesterase (PDE)-medi- ated cGMP hydrolysis is inhibited or cGMP synthesis is induced, e.g., by NO [5]. Cyclic GMP efflux was inhibited in the presence of 1 μM trequinsin, a highly selective inhibitor of PDE5 and of transport by "multidrug resist- ance" proteins 4 and 5 (MRP4/5). Transport was further inhibited by probenecid, an inhibitor of endogenous non-selective transporters as well as of MRP4/5 and by cycloheximide as an inhibitor of de novo protein synthesis. It, therefore, can be suggested that the expression of endogenous non-selective cGMP transporters and/or MRP4/5 is increased under elevated acceleration in human melanocytes and non-metastatic melanoma cells. Similar results were found on mRNA levels. In contrast, elevated acceleration does not affect cGMP efflux in highly metastatic melanoma cells. We propose that altered grav- ity should be regarded as a possible factor that may induce signaling events in human melanocytes via cGMP that could be important for malignant transformation. References 1. Romero-Graillet C, Aberdam E, Biagioli N, Massabni W, Ortonne JP, Ballotti R: Ultraviolet B radiation acts through the nitric oxide and cGMP signal transduction pathway to stimulate melano- genesis in human melanocytes. J Biol Chem 1996, 271:28052-28056. 2. Ivanova K, Das PK, van den Wijngaard RM, Lenz W, Klockenbring T, Malcharzyk V, Drummer C, Gerzer R: Differential expression of functional guanylyl cyclases in melanocytes: Absence of from 3 rd International Conference on cGMP Generators, Effectors and Therapeutic Implications Dresden, Germany. 15–17 June 2007 Published: 25 July 2007 BMC Pharmacology 2007, 7(Suppl 1):S31 doi:10.1186/1471-2210-7-S1-S31 <supplement> <title> <p>3^rdInternational Conference on cGMP Generators, Effectors and Therapeutic Implications</p> </title> <note>Meeting abstracts – A single PDF containing all abstracts in this Supplement is available <a href="http://www.biomedcentral.com/content/files/pdf/1471-2210-7-S1-full.pdf">here</a>.</note> </supplement> This abstract is available from: http://www.biomedcentral.com/1471-2210/7/S1/S31 © 2007 Ivanova et al; licensee BioMed Central Ltd.