Lesson 18: Intracellular Receptors

receptor guanylyl cyclase

converts GTP --> cGMP when NO binds

NO synthesis

NO synthase (Ca2+ cofactor) converts NADPH + O2 --> NADP+ + citrulline + NO

NO soluble receptor guanylyl cyclase end effect

smooth muscle relaxation

PKG

protein kinase G; activated by cGMP similarly to PKA

PKG targets (3)

1) K+ channels --> hyperpolarization 2) cation ATPase --> pumps Ca2+ into SR 3) myosin light chain phosphatase --> deactivates myosin heads

nuclear receptors

intracellular receptors that regulate gene transcription

sequence specific binding

structural motifls like zinc finger recognize surface features of major and minor groove

zinc finger

wraps around DNA major groove to recognize surface patterns

zinc finger structure

"𝛼-helix, small antiparallel β-sheet, and Zn coordinated with 2 His on 𝛼-helix and 2 Cys on β-sheet

"

types of nuclear receptors (2)

steroid receptors and metabolite receptors

steroid receptors

homodimers that interact with inverted repeat DNA sequences

metabolite receptors

heterodimers that interact with direct repeat DNA sequences

glucocorticoids

steroid hormones from adrenals in response to low glucose or stress

glucocorticoid receptor

located in cytosol and regulates anti-inflammatory pathway; associated with Hsp90 chaperonin in inactive complex

Hsp90

heat shock protein 90

Annexin 1

anti-inflammatory gene activated by GR dimer

NF𝜅B

dimer of p65 and p50; stimulates transcription of cyclooxygenase gene which causes inflammation

GR binding to NF𝜅B

binds to p65 domain, turning NF𝜅B off

why are steroid receptor signals long lasting?

steroids are not readily degraded and can accumulate in membranes and lipid droplets --> hang around for a while; takes time for products to decrease back to basal