Space Physiology
Head: Prof. Dr. med. Jörn Rittweger

Gravity and Cyclic GMP Levels in Melanocytic Cells

Human melanocytes function as a pivotal protective barrier against ultraviolet irradiation and oxidative stress by generating the radical-scavenging pigment melanin. In addition, several studies indicate that melanocytes are able to secrete a wide range of signal molecules. They also function in local immune reactivity as antigen-processing and antigen-presenting cells. Moreover, melanocytes in vivo are permanently targeted by mechanical stimuli, e.g., mechanical forces from external sources and mechanical forces via muscle contraction and growth processes. Recent data suggest that melanocytes are able to sense mechanical forces and transform them into biochemical signals.

Guanosine 3’,5’-cyclic monophosphate (cyclic GMP, cGMP) has emerged as a major focus in signal transduction research. Cyclic GMP is synthesized from guanosine 5’-triphosphate via activation of guanylyl cyclase (GC) that exists in a soluble form (sGC), the prime target for signaling activity of nitric oxide (NO), and in membrane-bound isoforms, that are ligands for natriuretic peptides as well as enterotoxins and guanylin. Mediating most of the effects of NO and of the natriuretic peptides, cyclic GMP plays an important role in smooth muscle relaxation, neutrophil degranulation, inhibition of platelet aggregation, neural communication in the brain, and several other physiological and/or pathophysiological processes, including inflammation and cancer. In previous studies we found that NO may modulate the adhesion of human melanocytes to extracellular matrix components such as fibronectin [Ivanova K, Le Poole IC, van den Wijngaard R, Gerzer R, Das PK. (1997). Effects of nitric oxide on the adhesion of melanocytes to extracellular matrix components. J Pathol, 183:469-476]. We recently found that normal human melanocytes and nonmetastatic melanoma cell lines express predominantly sGC, which appears to be associated with melanogenesis. In contrast, no nitric-oxide-sensitive guanylyl cyclase, but upregulated activities of the membrane isoforms of GC (GC-A and GC-B) were found in metastatic melanoma cells [Ivanova K, Das PK, van den Wijngaard R, Lenz W, Klockenbring T, Malcharzyk V, Drummer C, Gerzer R. (2001). Differential expression of functional guanylyl cyclases in melanocytes: Absence of nitric-oxide-sensitive isoform in metastatic cells. J Invest Dermatol, 116:409-416]. These results suggest that the differential expression of functional GC may be correlated with the metastatic potential.

As the risk for the development of cancer in human space flight is still not understood, we investigated whether cyclic GMP turnover is altered under variable gravity conditions. The results of our studies demonstrate for the first time that nonmetastatic melanoma cell lines respond to a long-time exposure (24 h) to hypergravity (2xg and 5xg) with elevated cyclic GMP extrusion, whereas metastatic cells remain insensitive [Ivanova K, Hamidi Zadeh N, Block I, Das PK, Gerzer R. (2002). Gravity and cyclic GMP levels in melanocytic cells. J Gravit Physiol, 9 (1): 271-272]. Thus, cyclic GMP appears to be important in the adaptation process of human melanocytes to gravitational stress.

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