Heterotrimeric G proteins are key players in transmembrane signaling by coupling a huge variety of receptors to channel proteins, enzymes, and other effector molecules. Multiple subforms of G proteins together with receptors, effectors, and various regulatory proteins represent the components of a highly versatile signal transduction system. G protein-mediated signaling is employed by virtually all cells in the mammalian organism and is centrally involved in diverse physiological functions such as perception of sensory information, modulation of synaptic transmission, hormone release and actions, regulation of cell contraction and migration, or cell growth and differentiation. In this review, some of the functions of heterotrimeric G proteins in defined cells and tissues are described.

https://www.physiology.org/doi/pdf/10.1152/physrev.00003.2005

Mammalian G proteins and their cell type specific functions

Disease-causing mutations often reveal key pathways of physiologic regulation and their underlying molecular mechanisms. Mutations in the trimeric guanine nucleotide-binding proteins (G proteins), which relay signals initiated by photons, odorants, and a host of hormones and neurotransmitters, cause many diseases. For the most part, the diseases are confined to a set of fascinating but rare endocrine disorders (Table 1).1 A recent study suggests that mutations in G proteins can also lead to essential hypertension.2 If this study is correct, hypertension may be one of several common disorders caused by defects in this ubiquitous family of signaling molecules. This review focuses . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199904013401306?listPDF=true

The Expanding Spectrum of G Protein Diseases

Drugs in every major pharmacological category can impair both taste and smell function and do so more commonly than presently appreciated. Impairment usually affects sensory function at a molecular level, causing 2 major behavioural changes — loss of acuity (i.e. hypogeusia and hyposmia) and/or distortion of function (i.e. dysgeusia and dysosmia). These changes can impair appetite, food intake, cause significant lifestyle changes and may require discontinuation of drug administration.

Drug-induced taste and smell disorders. Incidence, mechanisms and management related primarily to treatment of sensory receptor dysfunction.

The stimulatory G protein alpha-subunit G(s)alpha couples receptors to adenylyl cyclase and is required for hormone-stimulated cAMP generation. In Albright hereditary osteodystrophy, heterozygous G(s)alpha null mutations only lead to PTH, TSH, and gonadotropin resistance when inherited maternally [pseudohypoparathyroidism type 1A; (PHP1A)]. Maternal-specific expression of G(s)alpha in specific hormone targets could explain this observation. Using hot-stop PCR analysis on total RNA from six normal human thyroid specimens, we showed that the majority of the G(s)alpha mRNA (72 +/- 3%) was derived from the maternal allele. This is consistent with the presence of TSH resistance in patients with maternal G(s)alpha null mutations (PHP1A) and the absence of TSH resistance in patients with paternal G(s)alpha mutations (pseudopseudohypoparathyroidism). Patients with PTH resistance in the absence of Albright hereditary osteodystrophy (PHP1B) have an imprinting defect of the G(s)alpha gene resulting in both alleles having a paternal epigenotype, which would lead to a more moderate level of thyroid-specific G(s)alpha deficiency. We found evidence of borderline TSH resistance in 10 of 22 PHP1B patients. This study provides further evidence for tissue-specific imprinting of G(s)alpha in humans and provides a potential mechanism for mild to moderate TSH resistance in PHP1A and borderline resistance in some patients with PHP1B.

The Stimulatory G Protein α-Subunit Gsα Is Imprinted in Human Thyroid Glands: Implications for Thyroid Function in Pseudohypoparathyroidism Types 1A and 1B

Pseudohypoparathyroidism type I is a hereditary disorder characterized by resistance to parathyroid hormone and other hormones that work via cyclic adenosine 3′, 5′monophosphate (cAMP). Mo...

Bourne Hr

Papers

Pseudohypoparathyroidism: mutation affecting adenylate cyclase.