ORIGINAL RESEARCH—BASIC SCIENCE: T‐Type (α1G) Low Voltage‐Activated Calcium Channel Interactions with Nitric Oxide‐Cyclic Guanosine Monophosphate Pathway and Regulation of Calcium Homeostasis in Human Cavernosal Cells

ABSTRACT Introduction Nitric oxide‐cyclic guanosine monophosphate (NO‐cGMP)‐mediated relaxation of cavernosal smooth muscle during erection is accompanied by a decrease in intracellular calcium concentrations ([Ca 2+ ] i ). However, it is not known whether and how an increase in [Ca 2+ ] i is responsible for (i) initiating smooth muscle contraction/detumescence following relaxation; and (ii) maintaining the penis in a flaccid state under nonstimulating conditions. Aim To elucidate (i) the mechanism(s) of [Ca 2+ ] i homeostasis regulation in human cavernosal smooth muscle cells (HCSMC); and (ii) how NO‐cGMP interacts with such [Ca 2+ ] i homeostasis. Methods We evaluated the expression and function of both T‐type and L‐type Ca 2+ channels in HCSMC by employing selective probes/inhibitors using various cellular and molecular techniques (e.g., reverse transcriptase and real‐time polymerase chain reaction, cell proliferation assay, fura‐2 Ca 2+ fluorescence spectroscopy, enzyme‐linked immuno‐absorbent assay (ELISA)). Main Outcome Measure We have demonstrated for the first time significant interactions of NO‐cGMP with the T‐type (α1G) Ca 2+ channel in HCSMC. Results Our results suggest that in addition to NO‐induced rapid and transient decrease in [Ca 2+ ] i that results in smooth muscle relaxation, NO‐cGMP also enhanced mRNA expression of the T‐type (α1G) Ca 2+ channel resulting in delayed elevation of [Ca 2+ ] i . This could be abolished by a selective T‐channel blocker, NNC 55‐0396. Another unique finding of this study is that dose‐dependent HCSMC proliferation in vitro by NO is associated with the activation of the T‐type (α1G) Ca 2+ channel that regulates [Ca 2+ ] i homeostasis in these cells. Conclusions Human cavernosal cells express T‐type (α1G) Ca 2+ channels that are involved in maintaining [Ca 2+ ] i homeostasis and regulation of NO‐cGMP‐induced smooth muscle relaxation–contraction responsible for penile erection, flaccidity, and tonicity. Targeting these Ca 2+ channels may (i) associate various comorbidities with the onset of erectile dysfunction; (ii) provide a biochemical basis for differences between therapeutic profiles of various phosphodiesterase type 5 inhibitors, especially in nonresponders to current therapy; and (iii) provide biochemical basis in understanding mechanism(s) of drug tolerance. Zeng X, Keyser B, Li M, and Sikka SC. T‐type (α1G) low voltage‐activated calcium channel interactions with nitric oxide‐cyclic guanosine monophosphate pathway and regulation of calcium homeostasis in human cavernosal cells. J Sex Med 2005;2:620–633.