Male victims of sexual assault: phenomenology, psychology, physiology.

Myths, stereotypes, and unfounded beliefs about male sexuality, in particular male homosexuality, are widespread in legal and medical communities, as well as among agencies providing services to sexual assault victims. These include perceptions that men in noninstitutionalized settings are rarely sexually assaulted, that male victims are responsible for their assaults, that male sexual assault victims are less traumatized by the experience than their female counterparts, and that ejaculation is an indicator of a positive erotic experience. As a result of the prevalence of such beliefs, there is an underreporting of sexual assaults by male victims; a lack of appropriate services for male victims; and, effectively, no legal redress for male sexual assault victims. By comparison, male sexual assault victims have fewer resources and greater stigma than do female sexual assault victims. Many male victims, either because of physiological effects of anal rape or direct stimulation by their assailants, have an erection, ejaculate, or both during the assault. This is incorrectly understood by assailant, victim, the justice system, and the medical community as signifying consent by the victim. Studies of male sexual physiology suggest that involuntary erections or ejaculations can occur in the context of nonconsensual, receptive anal sex. Erections and ejaculations are only partially under voluntary control and are known to occur during times of extreme duress in the absence of sexual pleasure. Particularly within the criminal justice system, this misconception, in addition to other unfounded beliefs, has made the courts unwilling to provide legal remedy to male victims of sexual assault, especially when the victim experienced an erection or an ejaculation during the assault. Attorneys and forensic psychiatrists must be better informed about the physiology of these phenomena to formulate evidence-based opinions.

Structural determinants required for the bioactivities of prokineticins and identification of prokineticin receptor antagonists.

Prokineticins are cysteine-rich secreted proteins that regulate diverse biological processes, including gastrointestinal motility, angiogenesis, and circadian rhythms. Two closely related G protein-coupled receptors that mediate signal transduction of prokineticins have recently been cloned. The structural elements required for prokineticins' bioactivities are still unknown. We show here that both the N-terminal hexapeptide (AVITGA) and C-terminal cysteine-rich domains are critical for the bioactivities of prokineticins. Substitutions, deletions, and insertions to the conserved N-terminal hexapeptides result in the loss of agonist activity. Mutant prokineticins with the substitution of the first N-terminal alanine with methionine or the addition of a methionine to the N terminus inhibit the activation of prokineticin receptors and thus are considered as antagonists of prokineticin receptors. We have further shown that mutations in selected cysteine residues in the C-terminal domain result in prokineticins without biological activity. The essential role of C-terminal domain is reinforced by two observations: that peptides without the carboxyl domain and proteins with the N-terminal hexapeptide fused to the carboxyl domains of colipase or dickkopf are devoid of biological activity. We demonstrate that limited structural changes of C-terminal cysteine-rich regions of prokineticins are tolerable because chimeric prokineticins with swapped cysteine-rich domains between prokineticin 1 and prokineticin 2, as well as a splice variant of prokineticin 2 that contains extra 21 residue insertion in its C-terminal domain, are biologically active.

Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN) controls the circadian rhythm of physiological and behavioural processes in mammals. Here we show that prokineticin 2 (PK2), a cysteine-rich secreted protein, functions as an output molecule from the SCN circadian clock. PK2 messenger RNA is rhythmically expressed in the SCN, and the phase of PK2 rhythm is responsive to light entrainment. Molecular and genetic studies have revealed that PK2 is a gene that is controlled by a circadian clock (clock-controlled). Receptor for PK2 (PKR2) is abundantly expressed in major target nuclei of the SCN output pathway. Inhibition of nocturnal locomotor activity in rats by intracerebroventricular delivery of recombinant PK2 during subjective night, when the endogenous PK2 mRNA level is low, further supports the hypothesis that PK2 is an output molecule that transmits behavioural circadian rhythm. The high expression of PKR2 mRNA within the SCN and the positive feedback of PK2 on its own transcription through activation of PKR2 suggest that PK2 may also function locally within the SCN to synchronize output.

Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor.

We previously described two mammalian secreted proteins, prokineticin 1 and prokineticin 2, that potently contract gastrointestinal smooth muscle. Prokineticin 1 has also been shown to promote angiogenesis by stimulating proliferation, migration, and fenestration of endocrine organ-derived endothelial cells. Here we report the cloning and characterization of two closely related G protein-coupled receptors as receptors for prokineticins. Expression of prokineticin receptors in heterologous systems shows that these receptors bind to and are activated by nanomolar concentrations of recombinant prokineticins. Activation of prokineticin receptors leads to mobilization of calcium, stimulation of phosphoinositide turnover, and activation of p44/p42 MAPK signaling pathways that are consistent with the effects of prokineticins on smooth muscle contraction and angiogenesis. mRNA expression analysis reveals that prokineticin receptors are expressed in gastrointestinal organs, endocrine glands, and other tissues.