Molecular cloning and initial characterization of African green monkey (Cercopithecus aethiops) corticotropin releasing factor receptor type 1 (CRF1) from COS-7 cells

Słomiński

2010

Acta Biochim Pol

Alternative splicing of mRNA is one of the most important mechanisms responsible for an increase of the genomic capacity. Thus the majority of human proteins including G protein-coupled receptors (GPCRs) possess several isoforms as a result of mRNA splicing. The corticotropin-releasing factor (CRF) and its receptors are the most proximal elements of hypothalamic-pituitary-adrenal axis (HPA) — the central machinery of stress response. Moreover, expression of CRF and regulated activity of CRF receptor type 1 (CRF1) can also play an important role in regulation of local stress response in peripheral tissues including skin, gastrointestinal tract or reproductive system. In humans, expression of at least eight variants of CRF1 mRNA (α, β, c, d, e, f, g and h) was detected and alternative splicing was found to be regulated by diverse physiological and pathological factors including: growth conditions, onset of labor, during pregnancy or exposure to ultraviolet irradiation. The pattern of expression of CRF1 isoforms is cell type specific and recently has been linked to observed differences in responsiveness to CRF stimulation. In the proposed model of regulation of CRF-signaling, isoform CRF1α plays a central role. Other isoforms modulate its activity by oligomerization, leading to alteration in receptor trafficking, localization and function. Co-expression of CRF1 isoforms modulates sensitivity of cells to the ligands and influences downstream coupling to G-proteins. The other possible regulatory mechanisms include fast mRNA and/or protein turnover or decoy receptor function of CRF1 isoforms. Taken together, alternative splicing of CRF1 can represent another level of regulation of CRF-mediated stress responses at the central and peripheral levels. Chronic stress or malfunction of the HPA-axis have been linked to numerous human pathologies, suggesting that alternative splicing of CRF1 receptor could represent a promising target for drugs development.

Section: Hpa Axismentioning

confidence: 99%

Section: Crf Receptors and Their Ligandsmentioning

confidence: 99%

Section: Alternative Splicing Of Crf1 Receptor Regulates Crf Signalingmentioning

confidence: 99%

“…2) (Pisarchik & Slominski, 2001; 2002; Hillhouse & Grammatopoulos, 2006; Slominski et al ., 2006b; 2007b). …”

Section: Alternative Splicing Of Crf1 Receptor Regulates Crf Signalingmentioning

confidence: 99%

See 2 more Smart Citations

Emerging role of alternative splicing of CRF1 receptor in CRF signaling.

Słomiński

2010

Acta Biochim Pol

“…Recently we postulated that such a variety of phenotypic effects of CRF may be explained by cell type dependent expression of multiple isoforms of the CRF receptors type 1 and 2. 32,36,[75][76][77][78][79][80][81] At least…”

mentioning

confidence: 99%

Neuroendocrinology of the skin

Slominski

2011

Dermato-Endocrinology

Self Cite

More than ten years ago a comprehensive model of the skin acting as neuro-endocrine organ has been proposed. 1 Although the concept is still evolving, 1-7 it relies on the skin capacity to communicate with the central system and to regulate global homeostasis through local production and/or systemic release of classical hormones, neuropeptides, neurotransmitters and biological regulators (Fig. 1). 1 The skin is not only a classical source of vitamin D 8 but also a place of synthesis and metabolism of several neuropeptides including elements of hypothalamic-pituitary-adrenal (HPA), 1,9-12 and hypothalamic-pituitary-thyroid (HPT), [13][14][15][16] axes. Skin cells also possess fully functional serotonin-and melatoninergic systems [17][18][19][20][21][22] and express steroidogenic activity. 1,12 The presence of several neuropeptides and other biologically active compounds in the skin is due to both their local synthesis and active transport from blood or release form nerves endings or migrating immune cells. [1][2][3]23 The newly synthesized the concept on the skin neuro-endocrine has been formulated ten years ago, and recent advances in the field further strengthened this role. thus, skin forms a bidirectional platform for a signal exchange with other peripheral organs, endocrine and immune systems or brain to enable rapid and selective responses to the environment in order to maintain local and systemic homeostasis. In this context, it is not surprising that the function of the skin is tightly regulated by systemic neuro-endocrine system. Skin cells and skin appendages not only respond to neuropeptides, steroids and other regulatory signals, but also actively synthesis variety of hormones. the stress responses within the skin are tightly regulated by locally synthesized factors and their receptor expression. there is growing evidence for alternative splicing playing an important role in stress signaling. Deregulation of the skin neuro-endocrine signaling can lead or/and be a marker of variety of skin diseases. the major problem in this area relates to their detailed mechanisms of crosstalk between skin and brain and between the local and global endocrine as well as immune systems.

CRF1 receptor splicing in epidermal keratinocytes: Potential biological role and environmental regulations

Journal Cellular Physiology

Slominski

2008

Self Cite

Corticotropin releasing factor receptor type 1 (CRF1), a coordinator of the body responses to stress, is also expressed in human skin, where it undergoes alternative splicing. Since the epidermis is continuously exposed to the environmental stress, human keratinocytes were chosen to study the biological role of CRF1 alternative splicing. The expression pattern of CRF1 isoforms depended on cell density, presence or absence of serum, and exposure to ultraviolet irradiation (UVR). Only two isoforms α and c were predominantly localized to the cell membrane, with only CRF1α being efficient in stimulating cAMP responding element (CRE). CRF1d, f and g had intracellular localization, showing no or very low (g) activation of CRE. The co-expression of CRF1α with d, f or g resulted in intracellular retention of both isoforms suggesting dimerization confirmed by detection of high molecular weight complexes. The soluble isoforms e and h were diffusely distributed in the cytoplasm or localized to the ER, respectively, and additionally found in culture medium. These findings suggest that alternatively spliced CRF1 isoforms can interact and modify CRF1α subcellular localization, thus affecting its activity. We suggest that alternative splicing of CRF1 may play an important role in the regulation of skin cell phenotype with potential implications in pathology.