Molecular Yin and Yang of erectile function and dysfunction

Abstract

In regard to erectile function, Yin is flaccidity and Yang erection. In the past decade, research has mostly focused on the Yang aspect of erectile function. However, in recent years, the Yin side is attracting increasingly greater attention. This is due to the realization that penile flaccidity is no less important than penile erection and is actively maintained by mechanisms that play critical roles in certain types of erectile dysfunction (ED); for example, in diabetic patients. In addition, there is evidence that the Yin and Yang signaling pathways interact with each other during the transition from flaccidity to erection, and vice versa. As such, it is important that we view erectile function from not only the Yang but also the Yin side. The purpose of this article is to review recent advances in the understanding of the molecular mechanisms that regulate the Yin and Yang of the penis. Emphasis is given to the Rho kinase signaling pathway that regulates the Yin, and to the cyclic nucleotide signaling pathway that regulates the Yang. Discussion is organized in such a way so as to follow the signaling cascade, that is, beginning with the extracellular signaling molecules (e.g., norepinephrin and nitric oxide) and their receptors, converging onto the intracellular effectors (e.g., Rho kinase and protein kinase G), branching into secondary effectors, and finishing with contractile molecules and phosphodiesterases. Interactions between the Yin and Yang signaling pathways are discussed as well.

Figure 1

The erection cycle. Erection is initiated by sexual stimulation and maintained during continuous sexual stimulation. Erection starts to subside at ejaculation and the subsequent flaccidity is maintained until the next sexual stimulation. CSM, cavernous smooth muscle.

Figure 2

Signaling pathways leading to cavernous smooth muscle (CSM) contraction. Norepinephrin binds to adrenergic receptor, which then activates phospholipase C-β (PLCβ), and which splits phosphatidylinositol (4,5)-bisphosphate (PIP₂) into inositol trisphosphate (IP₃) and diacylglycerol (DAG). Binding of DAG to protein kinase C (PKC) leads to cavernous smooth muscle contraction. IP₃ binds to sarcoplasmic reticulum and triggers the release of calcium (Ca). Calcium (Ca) binds to calmodulin (CaM), which then binds to and activates myosin light chain kinase (MLCK); MLCK phosphorylates MLC, which then binds to and activates actin, resulting in contraction.

Figure 3

Signaling pathways maintaining cavernous smooth muscle (CSM) contraction. Norepinephrin, endothelin-1 and angiotensin II bind to their respective receptors, leading to the activation of guanine exchange factor (GEF), which converts RhoA-guanosine diphosphate (GDP) to RhoA-guanosine triphosphate (GTP). RhoA-GTP dissociates from GDP dissociation inhibitor (GDI) and migrates to the cytoplasmic membrane, where it binds to and activates Rho kinase (ROCK). ROCK phosphorylates and inactivates myosin light chain phosphatase (MLCP), allowing MLC to stay phosphorylated and consequently actin-contracted. Ag, agonists.

Figure 4

Signaling pathways leading to cavernous smooth muscle (CSM) relaxation. Sexual stimulation triggers the release of nitric oxide (NO) from cavernous nerves in the penis. NO diffuses into CSM cells (CSMC) and activates guanyl cyclase, which then catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP activates protein kinase G (PKG), which in turn phosphorylates potassium (K) and calcium (Ca) channels. Phosphorylation of K and Ca channels leads to an increase of potassium efflux, a reduction of calcium influx, and the dissociation of calcium from calmodulin (CaM), which in turn dissociates from the myosin light chain kinase (MLCK), thus inactivating it. Inactivation of MLCK and removal of phosphates by myosin light chain phosphatase (MLCP) lead to dissociation of myosin from actin and relaxation of actin.