MODULATION OF THE BIOLOGICAL-ACTIVITY OF THYROTROPIN-RELEASING-HORMONE BY ALTERNATE PROCESSING OF PRO-TRH

Thyrotropin-releasing hormone prohormone contains multiple copies of T RH linked together by connecting sequences. Like other plurifunctional prohormone proteins, pro-TRH undergoes differential proteolytic proce ssing in various tissues to generate, beside authentic TRH, several ot her novel peptides corresponding to C-terminally extended forms of TRH and connecting fragments. The pro-TRH connecting peptides are, togeth er with TRH, predominant storage forms of TRW-precursor related peptid es in the rat hypothalamus. Connecting peptides are co-localized with TRH in the median eminence nerve endings and co-released through a mec hanism involving voltage-operated Ca2+ channels. The connecting peptid e Ps4 is involved in potentiation of the action of TRH on thyrotropin hormone release by pituitary in vitro and in vivo through interactions with a specific pituitary cell receptor coupled to dihydropyridine an d omega-connotoxin sensitive Ca2+ channels of the L-type. It also caus es dose-dependent increases in the steady state levels of mRNAs of TSH and prolactin through stimulation of the respective gene promoter act ivities. These findings indicate that Ps4 and TRH, two peptides which originate from a single multifunctional biosynthetic precursor, can fu nction on the same target tissues in a coordinate manner to promote ho rmonal secretion. This suggests that differential processing of the TR H prohormone may have the potential to modulate the biological activit ies of TRH.