Receptor-mediated activation of Gsalpha: evidence for intramolecular signal transduction.

To investigate the mechanism by which cell surface receptors activate heterotrimeric G proteins, we applied a scanning mutagenesis approach to the carboxyl-terminal 40% of alphas (residues 236-394) to identify residues that play a role in receptor-mediated activation. We identified four regions of sequence in which mutations significantly impaired receptor-dependent stimulation of cAMP synthesis in transiently transfected cyc- S49 lymphoma cells, which lack endogenous alphas. Residues at the carboxyl terminus are likely to be receptor contact sites. Buried residues near the bound GDP are connected to the carboxyl terminus by an alpha helix and may regulate GDP affinity. Residues in two adjacent loops of the GTPase domain at the interface with the helical domain, one of which includes a region, switch III, that changes conformation on GTP binding, are positioned to relay the receptor-initiated signal across the domain interface to facilitate GDP release. Consistent with this hypothesis, replacing the helical domain of alphas with that of alphai2 in an alphas/alphai2/alphas chimera corrects the defect in receptor-mediated activation caused by alphai2 substitutions on the GTPase side of the interface. Thus, complementary interactions between residues across the domain interface seem to play a role in receptor-catalyzed activation.

Comorbidity in an inpatient eating disordered population: clinical characteristics and treatment implications.

Data are presented that describe the clinical characteristics of 96 patients treated at the C.F. Menninger Memorial Hospital, Topeka, Kansas, from November 1983 to June 1989. Their Axis I eating disorder diagnoses were as follows: 53 had diagnoses of bulimia; 21 had anorexia nervosa; 2 had both diagnoses; 17 had atypical disorders or eating disorders not otherwise specified; and 2 had a diagnosis of psychological factors affecting physical conditions. Seventy-three percent of the cohort were found to have either Axis I or Axis II disorders or both, comorbidity. Borderline personality disorder was found in 46% of the sample, although 20% of the patients with borderline disorders were diagnosed retrospectively. Depression was the largest comorbid Axis I diagnosis. Patient variables for sexual abuse, drug and alcohol addiction, purgative behaviors, and interpersonal relationships are also described. The authors conclude that a substantial subpopulation of eating disordered patients are significantly comorbid for other psychiatric illnesses. This high incidence of comorbidity may help explain the frequency of refractoriness of many eating disordered patients who do not respond to outpatient or short-term inpatient hospitalization. The authors recommend that additional research studies address the problems of the comorbid eating disordered patient and suggest that the findings be taken into account by clinicians and payers.